Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. eainhpbtentePME yohssadohrhptee sdsusdfravreyo diseases, of The variety a microbes. for abundance discussed low “inflam- is of with hypotheses role replaced the other potential be as and the should well hypothesis of perhaps as PHMHEC light and discussed, the in revision is (IWAI) between needs hypothesis, relationship infection” inflammation disease apparent sterile airway holobiont without body of united united the mation concept The the of the diseases. to systems related that analogous other and view autoimmune and is allergic, system which many immune to hypothesis, the con- leading from disease factor tax could underlying resulting and reactions an The stress infections be hypersensitivity psychological and processes. accompanying opportunistic and disease and physiological secondary to PHM exacerbate difficult Multiple tribute multiple could more of dysregulation even colonization/infection target. immune microbes long-term effectively colonizing and/or to the between immunosuppression differences make system en- PHM-induced Slight could immune be environment. microbes could the the reactions colonizing in sometimes for these microbes and Microbes identical and environmental disease. or virulence, system cause of similar their microbes antigens immune to increases abundance exposure the that higher low increased manner evade by which at a hanced by to encountered in means likely colonization/infection reactions or one hypersensitivity hypersensitivity-enhanced more be encountered cause would called be to newly mechanism system postulated would A microbes is immune PHM, according (HEC) the reactions. the contrast, the hypersensitivity of In thus era, cause some and disease. post-hunter-gatherer and least chronic system, the at debilitating immune during to hypothesis, human levels leading pre-agricultural here PHMHEC the without a proposed the with microbes in is to these coevolved lifestyle It to most that respond gatherers. with the generally or association be hunter-gatherers in during would in as encountered years decades age lived commonly million recent 200 ancestors microbes in the environmental mammalian occurred during that have their largely is microbiotas evolved and It these makeup humans changed. in genetic have which changes Human commu- activities rapid microbial human westernization. and as The with intense changed lifestyle. association have most urban to to the ceased or exposed that humans agricultural been postulated since the have an frequently humans in living (PHM), more that diseases began much microbes (microbiotas) autoimmune encountered and era nities hunter-gatherers are post-hunter-gatherer and that nomadic of allergic microbes as category in many live hypothesis, The increase includes microbiota westernization. here, altered the Al- with defined the explain association as of to in extension 2. hypothesis years an infections, involves 75 leading that last to and/or current phenomenon the common proposes triggers a is of here microbial factors part which era presented imbalances, 3 are post-hunter-gatherer factors hypothesis Microbial The are these (PHMHEC) Stress. that There 1. colonization/infection 3. and hypersensitivity-enhanced diseases: substances diseases. environmental microbe these autoimmune and/or of food and to all, allergic lergy/hypersensitivity not explain if to most, exist hypotheses Diverse Abstract 2020 5, May 1 Waterhouse Joyce allergic/autoimmune diseases in role microbes’ era Post-hunter-gatherer ffiito o available not Affiliation 1 1 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. a n eeal is,sgr atfos rcse od/eeae,sl n odadtvs ttesame diets. the plant-based At traditional and additives. foods food fiber high and foods, salt whole animal-derived foods/beverages, of saturated westernized consumption processed reduced The (especially foods, been fat fast included. has products, there sugar, also time, animal oils), are few last vegetable of antibiotics, the and like consumption in fat medicine, increased recently with contact western relatively includes associated in from typically to come be only exposures diet according to have New manufactured humans pollutants proposed that are outdoor years. been substances and that hundred from have indoor term made products both that often The to other factors processes, exposures years[9]. and developed of increased 75 petrochemicals diet, number last westernized of with a a the thousands includes associated include in It for to westernization observed effects. with here health been associated with used apparently increase be have rapid will diseases a westernization autoimmune been the and has with allergic there continued trend years[6–8], some is microbial This attention least of the at susceptibility[3–5]. focus Although in disease the imbalances being more affect cause effects subtle Even potentially here. microbial indirectly relatively body chronic presented latency[2]. to and sometimes hypothesis human of indirect HIV how the years subtle, of of of after more delayed ability toward parts system examination the various the immune an are in and the been communities examples on cancer[1] has well-known effects cervical Two there detrimental and causing delayed recently, its attention. in subtle, through more increasing virus illness the of papilloma uncovered, chronic been human focus affecting already to the of have been ability microbes effects become have the of have been interventions. us effects eye have effects given medical obvious naked more chronic and scientists has indirectly, the the health teeth, of and public with many of directly both As observe both surfaces through to microbes, microbes the the infectious small to many observe water control too to largely power pond organisms The of that beings. drop ways human a diverse from the everywhere exploring live that organisms 17 late the Since Introduction points Takeaway Diet Plant-based Health, cupational treatment. and research for Keywords: implications of discussion a with ending 3. 2. 1. oeo H nlgto h HHChypothesis. PHMHEC the potential of the investigating light from in dietary benefit PHM e.g., might of treatments PHM, role and the stress mechanisms immunotherapy. self- into avoidance, of Research allergen-specific as allergen elimination well and manipulation, the as methods microbiota aiding antigens reduction environmental treatments, be col- other anti-microbial may anti- PHM and changes, treatments PHM pollen of Various against effects food, reactions with antigens. negative defensive cross-react direct to system’s to that from westernization. exposure immune contributing gens with stem greater the be associated had could and/or may diseases have diseases years, onization/infection related humans autoimmune 75 and that and last autoimmune skin the Allergic allergic, the in in on especially rise and the period, air hunter-gatherer the the in since food, in Microbes uomue leg,Hprestvt,Mcoit,HgeeHptei,CosRato,Oc- Cross-Reaction, Hypothesis, Hygiene Microbiota, Hypersensitivity, Allergy, Autoimmune, th etr,we no a euehe rtdsoee h emn ol fmicroscopic of world teeming the discovered first Leeuwenhoek Van Anton when century, 2 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. erltd npr,t ieetmcoilepsrs h irbsascae iharclua rp and could crops possibly agricultural but with deficiencies[32], associated nutritional microbes The to related exposures. be microbial might were different this populations to that agricultural part, thought early in is related, that the exposures it be indications microbial to and the are society, due robust there agricultural decay an Interestingly, less to dental significantly[31]. change from the changed detrimental as suffer having such also lifestyle significant, food to were in in changes populations changes cultural change of communities. of first When North microbial resulting example beginning the in the In early the changes of one and to just was nuts one pre-agricultural. due is pine to changes, still effects This and led later but mutans[30]. acorns have sedentary of Streptococcus up to bacteria partially preview ground thought least humans a is early at provides consistency Pleistocene, were that the that change in at populations Africa, cultural And caused in of changes habitat. processing these different examples and food a the cooking, to and of moving use or One tool exposures[29]. changes of microbial climatic advent humans’ microbiota as the early human such like the in in occurred, reasons, alterations or Changes changes of hunter-gatherers cultural variety body[28]. nomadic points, the a as certain on for years and occur in million living did 200 microbes likely than with more for coevolved have control spent and that ancestors gatherers tissues[22,27]. methods mammalian of these their use in and the presence Humans observed and microbial typically diseases of different differences favor of the in number findings, argues reported a the contamination with been pla- research, for individuals has this the and responsible of individuals fluid[20], controls some are healthy contesting between synovial issues made in the been contamination sterile have lungs[19], laboratory arguments be the Although claiming to a brain[23–26]. blood[16–18], thought the with tract[14,15]. the even was person and including intestinal that centa[21,22] a communities, body human in microbial human as contain the the such to in in conditions, area roles certain after under beneficial Area problem play a only microbes of system. are of immune amounts others suppressed large while species of associated pathogenic, many generation are those that the Some including know to communities, led now microbial has We under diverse This for many hour drop[13]. an of in to understanding humans. accomplished continue be greater with likely now much will can and dollars costs billion data the dramatically. a dropped and than sequenced. sequencing more $1000, of were and cost a years genomes the 13 the species and human took rapidly, from animal the previously occurred wide arising and in advances What technology, technology a plant genes computer in microbial, on the for advances many all as and to Just of Soon, in due mapping 2000s[13]. live and learned early that sequencing been the complete microbes has in the the this allowed genome which of understanding Much Project, in Genome years animals. Human recent and plants in of made array been have Micro- advances on Great Window Millennia a the Provides over Revolution biotas Sequencing sections. later Genetic in The further is discussed be here will presented triggers, and other occupational hypothesis here, Several or presented The chemical/pollution hypothesis hypothesis. environmental the the microflora) of (aka with acceptance. role is microbiota compatible the of hypothesis westernization[10–12] to are altered A level related this from those of widest rates. including arising elaboration disease hypotheses, the inhabitants or in gained extension microbial increase an probably rapid human essentially has the normal explain that further the to explanation discussed attempting in be hypotheses changes not of regarding number will a it however, are westernization, There with associated often also here. is lifestyle sedentary A 3 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. oyhrmnsgniai a enipiae nbn osi u ies,adrcn eerhsget it bacteria suggests oral research recent abundance low and disease, the gum out[50], may in points species loss al abundant et bone since Lagier in important, implicated as seem However, been not has important. may gingivalis more species Poryphyromonas be rare species[4,41]. of to unusual knowledge thought limited and but be microbes. this occurring[53], rare rare surface, already many of the are detect improvements On detection to and possible problems, limit the not these and/or in still rectify discarding results to is present primers, made it and the (limited being known used bias currently be commonly are to practices already Efforts detectable certain must tend and yet species identified, rarefaction) not be the singletons, to and methods, order undetected, sequencing in libraries genetic still sequence most surface, with the addition, iceberg under an In diversity to similar or microbial as in rare the situation the methods. the found of regarding current depicted al[52] taxa portion information with are et inadequate large microbial Lagier methods is a body. improved of there the with other still, numbers inhabit of and but that the loss microbes methods microbes[50,51], abundance a extended rarer culturing low even to Better al[41] find followed[47–49]. lead et to have to detecting beginning Dethlefsen others seen of and difficulty 2008, been the samples, is has In recognized stool increasingly microbes, become many dramatic species/strains[46]. has that for have rare problem can fuel a advances, Diet a recent these is diseases[43,44]. Despite which tract[45]. varying some intestinal fiber, to in the of communities helpful in depleted microbial diversity be certain and diverse diet microbial with to normally diseases, a associated found the and been with been have deplete effects, have associated tract to probiotics intestinal and seen and the observed been in degrees[12], been have microbes Antibiotics Particular have made. microbiota diseases[42]. been human has the progress in rapid coevolution changes of evolved idea inhabitants. actually many the microbial microbes Recently, supporting their Some have further of to microbes. effects[40,41], many likely newer beneficial and is the other humans evolution of many and between have Thus, toleration exposures and allow genes. likely vitamins to microbial compatible seems extent, produce new more some to It the the to with DNA[39]. select least compatible ancient to at more using occurred, occurred done been have have would be and would selection to exposures variants natural microbial beginning genetic changed are developments human studies cultural some interesting past that although these in extent disease, Later, what And to to microbes, led strains[38]. known rock[35,36]. for them[37]. and not pressures of with is species selective it inside novel extracted unique Currently, of provided and be have number would depths could the that materials Microbes great increasing cultural new microbes potentially at human from used. thus new even made of being introduced products studied, part materials have cases, materials would as other the all coal with iron, virtually and associated and in petroleum microbes bronze living new copper, found introduced instance, are have the for likely not materials, would are different evolution and microbes, of environmental microbiota virulent effects. introduction human less chronic The typically the and/or on cumulative of focused post-hunter-gatherer subtle, part is the more hypothesis of be current with part The often as often sense, not hypothesis. that a this would diseases in of concen- epidemic they seen, focus causing be the However, microbes could and the smallpox) environment. agriculture of typhus, microbial many (e.g., of fact, period introduction In this the during animals[28]. accompanied arose domesticated diseases and outbreaks people epidemic many of many been tration a that have well-known there causing disputed[33]. however is theory, crops not this It are on on America that cast mold colonial history been in of throughout has trials doubt ergotism growth witch certain Some of Salem the grains[34]. to the is on that exposure grows role evidence that some higher historical is 17 much a there the context). played fact, be in the In likely would on ergotism[33]. depending has there called plural, that condition that or example singular sense is interesting the article An this in in PHM PHM (Note: been microbes. have agriculture-associated would storage their th etr eearsl ftehluiain n te ffcso h oisfo yeo fungus of type a from toxins the of effects other and hallucinations the of result a were century 4 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. novdi ubro iess h ehnssb hc hyaepooe ocnrbt odisease to contribute be to to proposed as are are rare they that so which and are altered PHM by PHM of the mechanisms definition the of The the of part fit all diseases. be that Not of microbes still the number of may westernization. in given a they abundance of be in however in years will involved low limits, examples 75 so detection and last be however, current the may undetectable, below PHM with significantly are these associated of be they microbiota may Some are that surfaces and diseases. lifestyle body skin/mucosal westernized autoimmune the human a and contacting of one allergic part and are be to ingested that might contributing PHM inhaled, some this substances least So, with at tissues. that associated cells. animal proposes human colonize/infect hypothesis predators. PHMHEC to within their the survival able of So, allow be inside might also survive larger use” survival PHM can by which “dual destroyed this actually by being allow to and avoid means that due amoeba, can adaptations as disease microbes such how the cause environment, generally describe And sometimes to the to and able used in being cells been predators humans? not has human microbial in as term within of persist That thought survive animals factors[64]. be in still may survival virulence may that for humans microbes adapted environmental healthy generally some not to infect that are leading recognized likely now disinfect that widespread, is to PHM at It is the used work of contamination products many its microbial cleaning could How do the cleaning, surfaces[63]. their to frequent on” copper in anti-microbial “feed afford despite living alternative to cannot species hospitals, of found microbial it investigation In been new but have found required rooms[62]. have planets, that is the NASA species other NASA at some to sterile[60]. scientists state- and Recently, truly microbes probabilistic cleanrooms[61] are cleanrooms. make transferring items level only of the highest Hospitals can chance if the but infections[37]. the determine cause methods directly to minimize sequential able cannot is to those multiple and this all with sterility kill though few items regarding to microbes, used thought a ments needed Autoclaves are for over sterilize besides but salty earth[36]. reach microbes to earth, on too they all everything attempt that kill Antarctica on in not earth in and places do the areas everywhere sterilization sterile in likely more for be deep are only the might so microbes also studied, the Otherwise, areas There are questionable[59]. other Probably they and Centigrade[36]. volcanoes more degrees tolerate. springs, discov- the 150 to hot new – are found But microbes cleanrooms, survival. are of laboratory microbial adaptability they to remarkable conditions conducive the time seem extreme highlight the not to at might continue occurring chemicals eries changes harsh cultural and other causation. products and changes disease of Man-made Significant agriculture in some involved why of civilizations[6–8]. been advent explain early have in can the could degree hypothesis accompanied and some this likely to rates, is PHM least disease the It at in contributing in present increase be apparently occurred. recent to were have rapid likely diseases the are these to explaining PHM hosts to some likely human addition least hypersensitivity. has In their at and PHM means and colonization/infection these coevolution through of PHM sufficient many disease of the of chronic to be lack between many to exposure the could coevolution of and that PHM period for disorders here The these enough proposed related methods. of long and current lasted some by allergic/autoimmune missed not least of been at have pathogenesis less could by the them The colonization/infection to many that typically contributing known. are proposes significantly are there hypothesis that and focuses environments PHMHEC main diverse distributions[55,58]. microbes The the of patchy plant of studies very one ecological with and are from often soil practices, known species[56,57], cultural is common rare human considered It likely be with hypothesis. should changing abundant, environmental are basis this are very of daily of that Some a biosphere become ones on vast question. to unknown skin whole to our as often this The with able abundant, so contact to abundant[55]. are into humans less come that relation in that environment being and living in their the ingest to for inhale, from biosphere[41], well-adapted we reasons microbes that rare so other are microbes the not be some called may are least sometimes there but at or microbes, body Presumably rare human body? of the human community colonize the diverse on the and up in make might diseases[54]. what other So, and disease Alzheimer’s in involved is 5 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. osuyteepnigae frsac aldAlronooy8] h td falrisi eainto patients relation in formed lower in been is allergies has rhinitis, of allergic force study especially task the protection allergies, a providing AllergoOncology[87], of cancer, in incidence called to the reactions research regard that allergic of With found IgE-mediated area Kozlowska[88] for microbes. expanding cancer. this role other the below, a and discussed study to bacteria As to pointing allergy. viruses, of is cancer, view research from microbes. this of to years, to description responses recent refer broader including to In this broader, discussion and even this responses,” become in defense now used host has be “allergic concept will as hypothesis reactions toxin allergic hypothesis[85,86]. to the this refers support as al[84] produced to substances et well continues and Palm research as irritants recent pro- toxins, arguments mechanism More venoms, sup- many defense i.e., insects. important done that substances, biting an environmental been concluding is by toxic has allergy research, from that research host the idea of the reviewed the tecting amount support al[84] significant studies et observational a and in Palm published, experimental damaging proteins was possibility. these hypothesis defense this and this host porting humans[83]. pathogens/pests, since many in plant’s decades allergenicity instance, the the protein’s For target Over the that allergy. to effects related against of of damaging defense be study hypothesis a might have the toxin as effects in to evolved the were era known reactions new substances called are allergic A allergenic that been peanuts that system. Profet[82] has was by immune diseases This the proposed allergic by hypothesis toxins. mistake the of a with study article. were began the this reactions allergy of of allergic history and focus the harmless the of essentially not most are for being or intolerances assumption one types associated called The as mechanisms newer often this Non-immune well or are as In to. reactions that referred allergy be immune being reactions that later. is adverse of will emphasize reactions discussed with types hypersensitivity to what immune as used major other of the be reactions, 4 of will much hypersensitivity the more allergy/hypersensitivity to immune however, term refer of The reactions, will types elucidated[80,81]. hypersensitivity IgE-mediated antigen. other word an immediate to the to on apply responding article, immune and may primarily cytotoxic, recognizing also (immediate, focus system described reactions immune will hypersensitivity the of section from types result to This major can lead binding 4 that that Once of antigens cell-mediated) one for complex, lock. just used a are is reactions allergen B fits Allergic term key system’s The a immune occur. response. like is to the can immune antigens bind that responses that allergic that particular inhalant system an learned responses), match to immune or allergic researchers other antibodies doctors food classical many level, The in a to occurs, mechanistic IgE to antigens. patients instance basic response called (for from a negative antibodies substances observers, aka dramatic At immunoglobulins, puzzled a produce such have others? cells have by and person well times one tolerated ancient would since Why known researchers. been have Allergies Hypersensitivity and Allergy its relationship their is opportunistic and hypothesis and cause underlying PHMHEC (xenobiotics) primary the chemicals/pollution the others are distinguishes stress, infections. and that cross-reactivity, What tissues[23,71–77] microbes allergy/hypersensitivity, the and/or of infections of with microbiota[78,79]. half blood sources slow the second gut the hard-to-detect, in regarding the and/or proposal microbes in that oral emphasizing proposals propose the some the to followed, emphasizing of have first Some Others the al[70]. diseases. means inflammation-related no 20 chronic by many the causing is be here may presented asthma, allergy, hypothesis with like connected conditions The intimately in are observed conditions. mechanisms is related proposed and and allergens/antigens These diseases to sections. autoimmune response later in in occurs detail that more inflammation in discussed be will th etr rs rmrsac yMtmn6–7,Bon6] eecie l6]adDmnu et Domingue and al[69] et Tedeschi Brown[68], Mattman[65–67], by research from arose century 6 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. olye ls10 eerhuigdul ln lcb-otoldcalnetsst dniyfo groups food identify to tests challenge placebo-controlled blind discussing worth double is it using hypothesis, PHMHEC research the to al’s[100] relation et in will cross-reactions as Loblay of diseases, role autoimmune potential the some illustrate least To section. at IgE-mediated later in just a not important reactions, in be hypersensitivity to to discussed of thought according be types are latex, many Cross-reactions involving in reactions. important cross-reactions allergic be some from to acquired least likely PHM at are latex of Cross-reactions to source rubber contribute a Natural could be trees. This could hypothesis. thus rubber PHMHEC soil. and from the community[98,99] and tires, collected microbial e.g., water some fluid rich products, air, and milky a many have the fruits make the to to of from found used variety derived substance been a is a has which and is of in adhesives, Latex effects syndrome, and allergens[97]. the more latex-fruit elastic latex because with called occur cross-react is is serious usually foods This cross-reactions additive. other more of abundant. that are as is set pollen foods well common pollen the Another cross-reacting to as and the food mouth reactions when occurs the the have year often to of the patients it exposures of swelling and cross- the syndrome season and proteins syndrome, the allergy allergy itching food in oral oral certain in strongly called of Thus, resulting is result allergies, This the seasonal reactions[94,96]. are immunology. pollens. with allergies of as patients food areas such diverse adult-onset in substances, in common inhaled important most this with are the Thus, reacting that that protein well[95]. cross-reactions thought as a known of is it targets examples is bind It allergen. that well-known to it pollen antibody many allergen instance, the IgE are pollen For with an There common cross-react found a structure[94]. to to study in said enough A similarity is similar a antigen infections. apparently to is parasitic parasitic that due fighting parasite antibodies in pollen, same a role a the of a like but plays microbe, allergen, infectious IgE an an that to target bind to bind both It antibodies can also cross-react[93,94]. produce lock. antigens might might to two one system If said only immune are antigens. fitting the antigens key similar Thus, two multiple a the to as antibody, bind specific same do as generally the quite antibodies to not that are found IgE, been like has antibodies, because occur Cross-reactions Cross-reactions next. discussed Cross-reactions be negative hypothesis. will proposed PHMHEC as the the antigens, of limited of much microbial to component that with due key here cross-reactions partly a proposed be to is are could related it effects however, be toxic any, allergens, may various if effects of little, toxicity with the substances ejection on to to research reactions immune related allergic irritating other are of diarrhea). from often existence or and that differ The sneezing toxic responses mainly coughing, extreme against responses sometimes (e.g., allergic mechanism and substance The rapid protective the produce microbes. of a to of ability of types their of in part variety reactions be wide and sections. a may later bacteria and responses in and substances discussed allergic viruses allergens be to bacterial IgE-mediated where will response Thus, situations that in other important are produced There be is to microbes[91,92]. IgE known infectious that controlling are in evidence of helpful evidence laboratory is found of it They now that also expulsion is have rapid there environment. others a that addition, And the responses[87]. is idea In well. allergic reactions with as the of allergic interface pathogens effects with for microbial protective that occurring but support cancer be tissues toxins, the may was natural and what dangerous there that organs only found suggests immunoglobulins[89]. not of data other and the of cancer research levels that against low concluded epidemiological unusual protective to an the due have are not who reviewed allergies patients is al[90] that that showing et cancer study of Sherman a level from increased comes an support have Further deficiency cancer. IgE of types some with 7 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. oteeprec ftesrs epne h omlsrs epnei omneprec n may and experience common a is response pressure, blood stress higher normal rate, contributes heart The or increased initiates breathing, that rapid response. something more for stress tension, used muscle the term anxiety, the increased of is include Stressor experience life tragic stress. the and of divorce, to sources conflicts, potential interpersonal commuting, all work, are life, events family to related circumstances Stress Difficult of producing Aspects be Physiological could and substances of Psychological potentially range antigens. and/or wider microbes’ noxious even and against toxins’ An the responses with defensive microbes. cross-reactions be to and could due toxins reactions reactions e.g., allergic syndrome which that exposures, latex-fruit to like appears dangerous as it cross-reactions, patients involving sum, among conditions In variability above. other mentioned for syndrome, with explanation allergy those the oral for of and symptoms part testing observed cause be in the Limitations also foods of could sense testing. make response. cross-reactions blood to treatment via Microbial hard in antigens is limitations the it by to identified, accompanied other antibodies been be and detect yet would to not exposures have impossible microbial antigens and makeup, microbial cross-reactions So, these genetic of responses. person’s most out. IgE-mediated the Since classical ruled with not not did vary were were they may they type that reaction but the some specifying involved, immune factors. were of thus causing of reactions reactions reactions, thus type immunological immunological intolerance The colonized, that However, food be had as may system. PHM reactions it immune particular food the involve the that not described where inflammatory al[100] an body with et responses. react the Loblay would of of system individuality immune the areas the explaining occurs, specific diet occur, symptoms. sometimes the the symptoms cells, in in where skin antigen in organs PHM response survive various a and the in to colonize of exposure and to part When able rashes, as are of PHM presence areas metabolize microbiota). these their in that plant to to proposes a able due hypothesis being or PHMHEC hypothesis (e.g., chemical, to The found the the due is However, with chemicals chemical provides cross-reacts certain also that that role. with PHM, where substance from microbiota associated a a antigens be play with producing might might by associated PHM suggested are them, system or they explanation. nervous with explanation plausible cross-react the The ap- chemicals a of individuals. the not that among responses were here, symptoms that the presented the substances of in levels involving variability regulation high cross-reactions as regarding with apparent well other foods as noted consumed all related also recently avoiding parently they al[100] also of time et had period another Loblay they a Interestingly, and reacted, improve, tea important. To they was salicylate time salicylates. substance high the So, that of to that of levels chemical. react be that high the might would food with containing salicylates difference one foods/beverages foods to the consuming this of sensitive just and that amount not person not, noted cumulative was would a They it the occasion, group. because but foods the one reaction, reacted, of in a on patient groups foods causing documented the was the al[100] whether what all et determine to determined Loblay to common that chemical difficult is a it context to made present due the apparently in work cross-reacted elimination resembled this anythat to and about have favorably infection notable responded not viral is patients did What the a for subjects of after criteria proportion the began the a of often yet met half Symptoms infection, diets. studied viral around symptoms. chronic Interestingly, being their a patients from later. causing disease symptoms were discussed of a foods be group ME/CFS), that will or the idea that syndrome of cause fatigue portion encephalomyelitis/chronic unknown myalgic A of (aka syndrome reactions. fatigue food chronic adverse cause that 8 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. viac hnmnnwssbtnitdi xeiet nmc[2,2] twssonta ieta were that mice that This shown to was substances. evolved It noxious have the mice[123,124]. may of in avoidance responses experiments cause to in IgE-mediated thus return substantiated of and was to responses. sensitivity phenomenon exposures time defense avoidance high dangerous now host extremely possibly is allergic of the it of anticipation how background, allow view a describes newer as al[84] the stress et of of Palm context sources the and in effects hypothesis stress populations[118–120], of PHMHEC many inhaled examples the in to these variability exposure of shown environmental rate all variability. been and With heart rate occupational has lower heart that It affected and found negatively recognized. rate al[122] matter et commonly heart particulate Magari less the athletes[121]. are raise young that can even stress different pollution of under air variability sources under that non-psychological rate substantially research. other heart of decreases are of area typically There unnoticed patterns new variability goes changing important rate generally an the that become Heart Analyzing rate has equipment. heart circumstances stress[117]. special the greater in with of fluctuation studied non- conditions of normal, be level of Under expected predictor can studied[116,117]. an a increasingly but is be been there to has variability, conditions, found rate stressful been heart stress, has of stress, measure chronic disease[112]. Another by heart affected for studies[113–115]. also factor several risk is in well-known which mortality a rate, pressure, all-cause heart blood resting high attacks[110,111] to increased contribute asthma An to initiate thought is or stress exacerbate Chronic infection[105]. can to also the susceptibility increase Stress the disorder, large increase stress disease[109]. recent and post-traumatic autoimmune A as developing such diseases. that autoimmune of disorders, say including stress more risk to conditions[103], that be observations of it variety to previous Suffice wide verified found a study is paper. exacerbate however, to this stress, found of after is Chronic consequences[105]. just scope Stress harmless. negative the not relatively long-term beyond general, is significant is in hours have or subject microbes to minutes this likely infectious for to of against lasting discussion fight lead stress detailed the to acute a during likely and important more attack, also was The an is conflict infection. response interpersonal fight stress when The to era prepared attack[105,108]. interpersonal as an everyday be physical in during response a to stress evolved stress been from psychological order to responses injury/infection has a in relevant stress the as during battlefields” just of since cells are to result occur conflicts, immune boulevards a that in changes described the as system infection to al[107] function immune an many “barracks immune et fight the in Dhabhar to from occur body that going decades[103,104]. changes the recent the prepare in as of that such gained understanding system crisis, greater pressure[105]. immune immediate much blood the the A and of with rate responses deal heart of animal injury[101,106]. increased array of an with case an along help is energy, is that It adequate there response provide ability Then, stress to system[104]. stress animals’ the sugar optimizing the immune in of blood to the play increased aspects to comes with evolved are it it relationship there role when intricate First, the considered of its terms be attack. and in to an response illness needs survive stress and on to the that of injury particu- research focused think in of be has to important area research role to much other its considered and whole are response: society, a stressors is modern everyday there in not these However, occasion- nature are but happen chronic people lion, only often most a that their by stressors by to that[102,103]. experienced of stalked due types stressors being detrimental the Psychological as as larly with such threatening deal animals. hormones, to life predatory stress evolved as of with animals release encounters that the like out of ally, pointed result response[101]. often a flight is as or It fight occur the responses triggers These then which palms. adrenalin, sweaty and mouth dry 9 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. epooe htsm ftesmtm xeine ndm niomnscudhv vle opromote to evolved have considerations. could evolutionary environments on damp based in environments experienced of the damp symptoms species favor to the Some discussed related would of recently PHM. disease some Daschner[133] evolution and include that of infections that might proposed as view well which He idea defense as dangers, reactions host the allergic of cause similar to supports range a able wide be infection to a as known of avoid are well fungi avoidance to as mechanisms to allergens, PHMHEC of related cross-reacting the development research to and hypothesis other PHM this to Some linking response thus response, a stress be flight stress. could or psychological fight norepinephrine the adrenalin). Elevated (aka of epinephrine part to effects hypothesis. effects as the its released microbial and in conditions, similarities are norepinephrine lung has elevated inflammatory Both noradrenaline) altered of to (aka number syndrome, Norepinephrine an a metabolic stress[132]. with of and of connections associated erythematosus hypothesized was lupus has systemic and noting including Research worth aged research mice of stress[129,130]. at epithelium[131]. line the chronic lung defense Another as of the of deficiency of result line invasion SIgA a first microbial of developed as and the spontaneously model community occur (COPD) as disease mouse to described pulmonary a obstructive found often chronic in is been resembling condition and has a antigens SIgA that showed other Reduced immunoglob- and an communication is barriers. antigens of SIgA is (SIgA). effects mucosal microbial there IgA the binds secretory cells, involves exacerbating that PHM. progression mast in above ulin of involved the on the effects in be involved section by negative likely likely the factor the burdened also Another and in is would responses later person that allergic discussed the system increasing nervous when be and the effective will stress and usual less as person’s cells and And, a mast which use addition, between stress, stress. In to physiological of harder stressful. more level more become even cause higher likely as will barrier would perceived mucosal This being strategies two the stressors invade. the coping and be psychological between to system to may feedback microbes immune lead a effects likely the likely more their will is suppress allow role, there can could a fact, stressors which In play psychological defenses[128], do Chronic stressors. physiological perceived. certainly stressors. of consciously life of effects be modern types the not to from may separate related still or to but stressors that and hard may such, psychological anxiety that responses as though or level recognized immunological even a uneasiness be So, important not at to might lead occurring that impulse can be avoidance hypothesis would microbes The stress PHMHEC and environments. the toxins certain the avoid harmful to of potentially impulse against as part the defense situations as a various as proposed perceive evolved and is sources it psychological likely threshold Thus, and would the physical colonization/infection to from words, PHM closer both other of be stressful. stress levels In would more higher by factors. they with affected likely psychological as those from would more environment hypothesis, stress conditions be PHMHEC the additional inflammatory cross- the any in and with to from stressors PHM people according effects the of negative Thus, to effects observable response having the body. of led for to the have level that susceptible higher of factors more a outside to to due be and leading partly inside be colonization/infection, allergens/antigens. could antigens PHM individuals of of reacting some sources level in other higher intense frequent more with a to is due along to response variability) partly PHM stress least rate to the at reason heart be exposures The could lower by article and response this throughout stress rate, discussed the heart diseases of of elevated range elicitation problems, wide observed a the sleep in Thus, anxiety, occur that increased response. stress (e.g., a effects produce connection potentially stress also the would shown allergens/antigens have the PHM-associated also reactions[126,127]. in allergic The studies hormone allergic human with classical stress-related and addition, a areas on disorders In of avoid neuropsychiatric dependent level allergen[125]. elevated stress-related ability to the be an the between to tended detecting to confirmed exposure have by and found the rats stress following and were increased it brain mice cause behavior to in to experiments on exposure exposed Additional allergen effects when cells. of These mast anxiety and of IgE allergen. involving signs mechanisms the showed of allergen amounts egg trace an to sensitized 10 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. uaseovdwt.Teemcoe,wt hc uasadteracsoseovdfrmlin fyears, of millions for evolved ancestors their and that humans environment organisms which parasitic natural some with the to include microbes, the beginning of may also appear These components the Instead, This other that with. after hunter-gatherers. evolved and infections. as microbes humans humans plants to childhood affected exposed the soil, aforementioned widely from that were that the humans mainly infections that is includes are “crowd” studies which microbes so-called beneficial settlements, recent the proposed large by not and supported are agriculture is benefit of and some sense offering more infections. be avoid that makes consequences[11]. to concern not health try of what not did public matter Instead, should vaccination serious a they to been of that has lead meaning era it could as the fact, hypothesis clearly For hygiene In before This the illness[10,11]. hypothesis. experienced interpreted hypersensitivity-related have hygiene were of people the that level some reduced of diseases a form and, allergens. childhood to way this harmless lead usual proper contradicted as the the such that having in to, observations trained instance, react reported not to not studies explain is should exposed The further system it to are However, immune that updated. human proposed societies antigens PHMHEC the been to westernized often that the reacting has modern is means is to westernization, in this therefore, which with and related living hypothesis, now, associated individuals are infections hygiene diseases that fewer hypotheses the autoimmune postulated and and that hypothesis[135] diseases allergic mention hygiene various in to how increase important au- about the is allergic, detail it in more hypothesis, into increase going the Before explain to diseases hypothesis inflammatory hygiene and the toimmune of form Updated treatment effective more of provide development could the guide hypothesis help PHMHEC immune could the which include And potentially approaches. diseases, might that diverse discussed. for being effects infections framework diseases unifying PHM opportunistic the a of The to cross- many susceptibility exacerbate and symptoms. increase and/or PHM trigger diverse then to for can hypersensitivity account that with together suppression/dysregulation potentially infection, can rule PHM antigens can to methods reacting test leading new immune one revealing sometimes is no of colonization, research that PHM Recent types so diseases. other mechanisms evidence autoimmune reactions. diverse and in increasing these of found Allergy detecting is result increasingly of a are There common. they as and diseases. is occur out inhalants inflammatory sources them and chronic many foods many from to of antigens hypersensitivity rates proposed among increased are cross-reactivity is the “sick of chemicals/pollution controls, that diet, in environmental healthy support westernized involved and in a in even be settings from body, found to occupational microbes the era environments, being of holobiont post-hunter-gatherer damp tissues (united is to all body buildings,” evidence Exposures in the possibly increasing supported. of microbes, being parts section, of increasingly different compatible presence this affect is The that in that hypothesis). diseases way points disease chronic a many main in between the interconnections years diseases of the 10 related many last and the summarize inflammatory over To autoimmune, evolving allergic, been hypothesis. of has PHMHEC variety areas the a diverse with of in overview research and how an showing give will Diseases section Hypothesis This Inflammatory PHMHEC the and to Autoimmune Related Concepts Allergic, of Survey (e.g., subconsciously others or and consciously themselves individuals infecting avoid of responses sick[134]). animals avoidance behavioral be of other and study to and detection the perceived humans from behavior, help arising sickness research to carcasses, of evolved field avoiding have a to also is appear There that fungi. by infection of avoidance 11 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. nemtetcnaiainta ol edt iia ies rcs.As,i ih eta rmr or primary or a constant that be to con- might lead but it might body, Also, the body process. in disease the similar reproduce from a to antigens to unable microbial lead could be the that might removing contamination coloniza- difficulty microbes intermittent cases, the or and other colonization/infection, because re-exposure however, In enhancing tinual occur system; colonization/infection. without not immune present hypersensitivity-associated might the be HAC, evading tion/infection may considered hypersensitivity for be of mechanisms might form the this some contribut- of are cases, one PHM some that Hypersensitivity- in be proposes colonization/infection. may it chronic level, colonization/infection slow, basic typically enhanced most through the diseases At inflammation-related to variants. ing environ- several has inflammation; hypothesis PHMHEC sterile The vs. IWAI exposure hypothesis; chemical a implications mental PHMHEC category have which the might clear and of be purposes Variants not heuristic may environmental for it primarily helpful cases, are few be which a could PHM, In categories of in research. the hosts. categories further for healthy but have 2 discussed that in in, first be virulent activities belongs the not different less on will microbe not much of based category might variety are is third a that that hypothesis This to microbes microbes this due era. infectious as common post-hunter-gatherer virulent article more the other this be in include might common might like but more after individuals, settlements also become arose healthy large It in that to diseases infections smallpox. related acute crowd be and cause of that plague causes microbes bubonic the includes plastics the and are settlements to category, large adapted PHM” like and “crowd/virulent be agriculture strains, the might category, and that third species those The discovered and category. recently materials. cleanrooms[141,142] novel PHM” or “novel or relatively uncharacterized the other solutions novel, abundance and cleaning being low their in to the discovered due PHM of those are many that time those includes long are This a microbes consumed of category the are second they environment: The when post-hunter-gatherer products a salt- agricultural in in in increased fungi increase harvesting. be Archaea[139], that after (salt-loving) to microbes halophilic proposed tends and are pneumophila, exposure fish[140] that Legionella microbes that preserved e.g., those fact category, are the category PHM” first to The “increased due PHM. of PHM categories be three to describe to helpful be may microbes It diseases era many post-hunter-gatherer in associ- rise of PHM recent categories to the Three exposure for explanation increasing the that of here part inflammation. proposed significant chronic is source and a it the dysbiosis be addressing Thus, involving could but changes, westernization important. name inflammation-induced with also the the ated is given of microbiota effects inflammation the been the manipulating families the has mitigate or Firmicutes of help microbiota probiotics may and the polyphenols, products Bacteroidetes antioxidant of its the as or state such from to the imbalanced reactions strategies, oxygen of This Treatment hypersensitivity tolerate bene- to microbiota dysbiosis. not surviving[137,138]. related of the indirectly difficulty do loss environment or in that more or directly inflammatory have species imbalances is reduction oxygen-rich that beneficial of an the threat Then, development microbial that to PHM. a the proposes contribute counter that by to hypothesis may proposes arises exemplified PHMHEC and often it The is well and as proposal issue, tract. role important This gastrointestinal an important as an microbes. microbes play ficial some may in exposure reduction PHM accepts Old hypothesis and PHMHEC hypothesis[12,136], The depletion microbiome microbiota altered or autoimmune the and microbes including allergic ways, hypothesis[11]. missing of several Friends level hypothesis[10], in increased described microflora an been to altered has leading or hypothesis be hygiene to revised hypothesized This is this diseases. and missing, or reduced are 12 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. hr r ievreyo iesso h eprtr rc hthv okonifciu as;however, cause; infectious known no have that tract when respiratory sterile the the be in of to than diseases thought communities[147]. impact of previously microbial variety an diverse were wide of harbor lungs a more to are The known had There are lungs. methods now the sequencing but especially microbial disease advanced tract, of free of respiratory impact the the of PHM. study has the of area effects no the In from PHMHEC indirectly the or diseases directly of of arise respiratory role perspective that the Noninfectious the processes to and complementary the from discussed, be of However, to might observations part article explanations be the valid. this mechanistic might of of or be or each hypotheses scope PHM still other for the the might of beyond offered how role explanations is show been the take other It have to hypothesis, will aims cases, that hypothesis. review it many PHMHEC hypotheses following categories, the alternative the in not disease research, to the and different of related all hypothesis range in are consider PHMHEC broad fields commonalities the a diverse emphasizing cover regarding in by to evidence advances and order the approach, In to survey justice here. a do for. included to called be review seems can to affect everything research they much environmental that is in might body present There infection,” the microbes apparent abundance of low without tissues on “inflammation research the IWAI, Future that and acronym inflammation. something chemicals the sterile is this, replace sterility to of verify used light truly that be to In silica techniques, considered. current the of be in sensitivity should products limited interesting silica. the microbial be with of or impossibility, effect would microbes The cell the it abundance in however 2 low involved inflammation, type be be Mycobac- sterile also helper also control as might to could T there system described a immune whether been the induces investigate of has to silica ability multiply. This the to to on PHM tuberculosis[146]. effects exposure needed the detrimental terium time occupational has for that long that needed it correct, response the time indicated immune is that and (Th2) the study hypothesis time to significant recent PHMHEC related long often the a for partly is the Interestingly, If need be exposure of could potential infection. xenobiotic develop issue the an the to and the include with disease mentioned, might review, for along also which same occurring was hit, exposure exposure is the second xenobiotic PHM it In a with after However, like along develop factor, out[144]. occurring article. to until another exposure ruled this disease microbial to for of be that takes acknowledged possible exposed scope not often subject the of on not could the beyond number Research were of exposure is review a humans PHM. xenobiotic recent mechanisms to a that to these that pointed chemicals related of noting has worth discussion from reactions autoimmunity a resulting of in and inflammation place xenobiotics (PCH), recently[143–145] include or the hypothesis chemicals that take hypersensitivity factors environmental mechanisms exposures chemical other of chemical or era role PHM to post-hunter-gatherer the which related the in reactions situation is a where hypothesis of is context related generally possibility the dysregulation. Another least Another and/or in at themselves. suppression only by immune or but disease caused disease with chronic already to coevolved significant had contribute be cause that could post-hunter- to microbes presumably they environmental unlikely be would that most and microbes evolution since likely, humans the throughout enhanced less by seems that to tolerated PHM hypersensitivity it require exposed in possible, regarding not is were difference hypothesis this would humans inherent Although this it no microbes. since of hypersensitivity-enhanced era is microbial hypothesis, gatherer aspects the there MHEC called that other be or might is yet variant colonization/infection This hypothesis microbes, apply. PHMHEC still other might the colonization/infection to to still related opposed could is the as PHM or that the occurs view cases, down-regulation Another latter or these exhaustion effects. inflamma- In system negative or immune having suppression. hypersensitivity as be immune The time increasing hypersensitivity. over produces no decline or colonization/infection might little also to response lead tory might deficiency immune secondary 13 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. amokr swl stoewohv oko obe novn id,aemr ucpil oHP[166]. to susceptible more are birds, involving hobbies or work have who those as exclusively well hypothesis. were ex- as PHMHEC humans Farmworkers the are when environ- with there occupational/built occurring compatible and operation, exposures are diseases farming from between exposures the respiratory intensive connections ment differ Whether these an recognized that frequently or of later. chemical, These dwelling many and discussed hunter-gatherers. moldy across microbial conditions factory, both theme inflammatory building, posures, and unifying office autoimmune important an other is an environment as be well to as seems diseases[164,165] connection occupational The microbiology discovered. environment 60 been diseases found exposure/built have for study antigens Occupational implications relevant The all potential that hypersensitivity in has biosphere[161]. asthma, unlikely this as were important, rare is such that that conditions, it the be of noted sarcoidosis[163], methods variety of a can and and on for part pneumonitis[162] mentioned cavity based species been clearly oral point has undetectable were As the similar hypersensitivity. even stated involving in a they made rare, genera which article fungal that with recent fungi, nonpathogenic idea asthma abundance A detect in severe the to low hypothesis. that too supports able PHMHEC are showing the This fungi studies the with by when accord even detected[158]. suggested highlighted. therapy also anti-fungal is be by is in microbes in to ameliorated asthma research rare be area in new can of unexplored diet the sensitization and relatively role fungal of microbiota and some important gut discuss exciting potentially the they is an The of and as response as role investigated agents defense intriguing allergy be The infectious host of to allergic for models. view beginning the roles murine new are to established mechanisms this related discussing potential describe research After which authors newer pertinent. The asthma, is in review exacerbating discussed. factors a asthma or hypothesis, exacerbating on triggering PHMHEC and al[158] the of triggers et of discussions perspective Earl with the by From replete paper agents[158–160]. is infectious diseases well-known respiratory of effects diseases, noninfectious the the of on some nonin- Research least be reactions, at hypersensitivity to In and considered microbes microbes. been between of interrelationships cross-reactions. historically potential role has including of important appreciation diseases the apparent greater these of a an is of understanding there growing origin to a the lead is though there can or below, fectious, trigger mold discussed the of be will sources fatal. of medications, As like avoidance to immunosuppressive exposures, where curable environmental is HP[157]. essentially setting, known in diseases from to occupational e.g., respiratory related ranging the cure, those prognoses, these in are varying often of prognosis widely to Actinobacteria, best all are secondary the nearly there be with in and Those to found corticosteroids, used as been treatment sclerosis[156]. such has systemic of lungs and type arthritis the rheumatoid in A as inflammation such include id- cases, disorders diseases[155], and tissue some (HP) lung connective In pneumonitis autoimmune inflammatory hypersensitivity fibrosis. labelled sarcoidosis, pulmonary diseases, including iopathic conditions respiratory noninfectious chronic And apparently diseases[152–154]. of likely rhinitis[153]. many these non-allergic category more between or connections are broad allergic the rhinitis Another have documenting allergic patients studies asthma with other of those many majority instance, are exemplified the For as there and conditions, these hypothesis[150,151]. asthma[152], between develop linkages disease the to airway of appreciation united growing the a con- by been production has nasal mucus there years, as and recent such inflammation In involves symptoms rhinosinusitis includes airways. chronic often rhinitis upper And and Allergic the eyes. intermittent in triggers. involve watery more and diseases other generally sneezing Both or being gestion, chemical disease. asthma allergic, pulmonary with with obstructive airways, chronic category associated constricted and One through asthma breathing infections[131,148,149]. includes difficulty low-grade which chronic disease, resemble airway that is processes inflammatory involve they 14 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. oeaueifcin n/ricesdpyhlgclsrs ih cu,eaebtn h ies process. disease the exacerbating or occur, one might Then, stress psychological environment exposure. increased the environmental and/or from higher-than-usual could PHM infections hypothesis a be symptoms. PHMHEC acute after The persisting to more sometimes these remission[184]. reported and individual, in disease the is been the disease colonize/infect fatigue of has lung severe development the and disease systemic neuropathy after the the fiber persist explain small may from conditions, that pain found mortality chronic been addition, and have In sarcoidosis years[184]. recent of needed, in increasing severity is average research the Further Interestingly, diseases[177,182,183]. trials. inflammation-related by sarcoidosis controlled and in randomized system promise (1,25- autoimmune shown including D immune has other vitamin blockade diseases[177,181]. the active hypothesized inflammatory some of this suppressing other overcome ratio some and to be high and attempts sarcoidosis the that might in of approach found treatment infection cause typically A the (25-D), polymicrobial D be vitamin could the inactive This to in D) receptor[177,180]. microbes antimicrobial D antimi- vitamin the the typical the aiding of the blocking in more effective that very or mean be One could not pathogens. would This the system combat immune to colonization/infection. the medication since PHM crobial successful, of suppression/dysregulation the be immune many not of of might so level result approach some why treat. a frequently explain successfully is as there to could occurring that and network proposes understand causal hypothesis to PHMHEC complex PHM difficult coloniz- The polymicrobial This so The the a been including PHM. with have bacteria[179]. [159], the diseases cross-reactive and infections chronic of or fungi opportunistic these identical role secondary with be be the e.g., also may from infection, could hypersensitivity arising NCT02024555). There causing (see interaction PHM. antibacterial yet environment ing/infecting complex ongoing reported the a been one in not proposes is antigens have hypothesis results there but PHMHEC and completed The just promise, was Antifungal[175] some that one shown acnes)[174]. mycobac- and have Propionibacterium nontuberculous trial[178] as approaches (formerly such bacteria, acnes antibacterial[176,177] for Cutibacterium role and sarcoidosis. causal and in a species[149,174] suggesting of components research sensitivity wall terial been greater cell has a bacterial there for sarcoidosis, and evidence In fungal found been to study[172] has cells A Sarcoidosis mononuclear environments[173]. discovered. blood give damp were antigens in They peripheral conditions HP. inciting exposure as the from mold pneumonitis until to inseparable” hypersensitivity sarcoidosis linked fluid as pathologically metalworking diagnosed and and originally “clinically proposed were disease New- have often that beryllium antigens[172]. authors chronic is environmental of some sarcoidosis to examples and hypersensitivity that the organs, or state infection[149,171] other al[163] chronic affect et to may man related also last be that and could may disease it that increase lung that illnesses idiopathic colonize, progressive an the serious to is to not potential Sarcoidosis lead are the to smoke have potential cessation. high smoking are in microbes particularly after researchers chemicals Since a long and many have smoke would role[168–170]. the cigarette they in their COPD, mutate, abundant investigate like are and to diseases, Microbes asbestos beginning smoke-associated components[168]. silica, damaging idiopathic as tobacco such potentially in of substances only key particular case be to the linked might In be microbes to and known dust are that organic Synergistic those and beryllium. antigens. as inorganic PHM non-microbial well and of chemicals, as antigens effects conditions of microbial the combinations cases, to not many of addition have in antigens in effects that relevant possibly suggest with involved, the would are associations but hypothesis have colonization/infection tetrachloroethylene[167], PHMHEC to and The found dust discovered. a are metal been pneumonia, in as fungi. interstitial such occur and idiopathic exposures dander HP like lung occupational animal and conditions, for grain, idiopathic sources asthma dust, some well-known Occupational wood Even are chemicals, humidifiers, involving complex. and industries avian tubs of mycobacterium hot range from of wide use disease the including as diseases, such activities occupations, Besides 15 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. xoue r uttetpo h cbr fevrnetlmcoe’iflec ncrncinflammation-related chronic occupational on that influence suspect microbes’ per- to environmental the of reason with iceberg is the of But there of research, diseases. groups exposure. tip growing are the of the just there levels and are because extreme hypothesis, exposures antigens sometimes PHMHEC rich disease-provoking and the potential revealing distinctive, of find often spective are to similar, surfaces have easier who damp is bathroom employees frequently it Mycobacteria, and other studies, of kitchen of occupational strains studies and In molds[196]. And of drains[198] as hazard[197]. dozens like threat health environment found a a communities[199,200]. showerhead built serious microbial be a the might as on some in just bacteria, that biofilm locations be some suggested microbial and since authors buildings. the rectified[195,196], responses the water-damaged of and immune be of should greater study investigations that cause a oversight Interestingly, can in an used Mycobacteria, attention is commonly as much this by such that as missed suggested received be have easily not Researchers could have play and might bacteria environments PHM Historically, abundance damp low in seems increase it microbial would methods. but measured this[162], detection too and explain et microbial they features to Mendell disease since theories studies, between of role, several relationships number a clear in a find are symptoms to There or difficult rates exposures. was disease it that increased noninfectious noted rhinosinusitis[162]. with of al[162] chronic associated range and was a rhinitis dampness of allergic Although exacerbation HP, or asthma, development as the These such with growth. diseases, and bacterial associated respiratory and lung been fungal viruses have increased the to to environments parvovirus[194]. in lead damp environments responses and reactions damp virus[92] IgE-mediated other abundant immune influenza and but provokes be buildings zoster[192,193], Water-damaged studied, varicella Archaea to little HIV[191], Archaea the human for been shown of of found have have one cause been allergens al[189] showhave found important Viral et reviews They research an Lecours Recent tract[190]. is is environments. gastrointestinal example HP[188]. agglomerans scarcity. farm One and Pantoea a some asthma remedied[187]. pathogen, than in as be plant to such rather bacterial beginning diseases factors and common is respiratory historical hypothesis allergens a PHMHEC to microbial that the due identified but showing in is far, deficit this so this identified that that allergens suggest microbial trends non-fungal current few respi- relatively chronic are in There infections and are colonization beneficial of diseases be role ratory The might the that and species/strains. Microbes allergy/hypersensitivity the disease. Microbial apparent. in cause is to novelty could environment and exposure that built diversity including those the to conditions, with authors of adding harsh intermixed of microbiology The forms, how diversity the mutant the out were of underrepresented to pointed classified[186]. complexity that greatly lead al[185] be still could microbes et study not Horve solutions, of their addition, cleaning could species methods, In advanced information 2500 of over exposures. DNA use microbial identified the their devices far. despite of sampling so that 43.7% identified wearable noted remarkably, been using have and, persons allergens hypothesis. encountered, 15 bacterial PHMHEC of of the dozens study inhabi- with and microbial compatible A fungal is the discovered 150 on skin being over done the is that being on that noted is much or They that and air research environments, important. results. the built groundbreaking is of the better in tants exposures reviewed obtain food, microbial al[185] to the of et approaches in Horve range antimicrobial Recently, PHM wide with a of synergistically perhaps of sources work disease, study potential and depth respiratory to recovery In overt the exposures symptoms. more in of systemic the help reduction cause might cases, and that remain some be might In might PHM the infections It but secondary disease. improve, and of might colonization infections, signs further secondary overt and from more reactions largely hypersensitivity to of leading cycle vicious occurs, a point, that At 16 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. eentaudn rvosy n yesniiiyt hmmgtaetteaiiyo .tbruoi to tuberculosis M. of ability that the with, affect cross-reacts human might it pre-agricultural them that in environment to found the modern is hypersensitivity immune it our in and the since in previously, mycobacteria PHM of PHM abundant a related are ability not not closely there were is the abundant perhaps tuberculosis an take reduce However, M. to disease is even might much tuberculosis. remains[210]. part, It might mycobacteria M. so in control environmental and cause disease. to least to cross-reacting PHM system to at tuberculosis These as lead Mycobacterium relate, to qualify of might environment environment. also ability the areas would the poverty-stricken in that microbes in microbes consider opportunistic related to the closely possibility manner. interesting of with complicated cross-reactions some more and of that advantage harder-to-detect possible subtle, sys- more immunosuppressive is immune a an the It play on in might although PHM effect HIV, detrimental The a to infections[209]. is analogous opportunistic there role overt HIV-AIDS, multiple In underlies appropriate. that be cause tem abundance might not low AIDS do with potentially analogy and disease. factors, An frequently of other present cause are that underlying species suggests the these are carriers[208] of PHM, asymptomatic many in aeruginosa that Pseudomonas symptoms Some fact influenzae, PHM. noticeable The Haemophilus by as dysregulated pneumoniae. such or bacteria Mycoplasma suppressed features are and is virulent species system more opportunistic have immune such that the of microbes which many examples in that from situations expected of far to be advantage would take is reactions it would valid, in allergens for is hypothesis than bacterial testing PHMHEC greater the only of If significantly were characterization percentage they by previously, since mentioned a work underestimate, as CRS, cite an with and complete. They probably patients allergens, is of bacterial antibodies hypothesis. this IgE 37% known However, that barrier in exacerbating found likely allergy present immune rhinitis. al[207] is were allergic bacterial the colonization et bacteria bacterial Calenoff of of that for allergy. concept concluded part bacterial specific and the involving as polyps mechanisms nasal (CRS), al[206] through with rhinosinusitis inflammation CRS et on chronic Bachert al[207] disease, et by Calenoff respiratory included pneumonia. another the than been to people of has susceptibility younger case the healthier, and underlying the in in the syndrome In enough pneumonia be building and/or to significant sick acute hypothesized the Dysregulation been cause water be both have to tower might of symptoms. could pneumophila colonization/infection cooling cause syndrome syndrome and L. the allergy/hypersensitivity building allow building PHM in sick to sick usual. workers the PHM the the from that in of system suggests role some immune hypothesis causal the PHMHEC a of the played suppression were study, conditioner symptoms above air the maintained the and inadequately staff, to the the relation considering cool- of syndrome the In system. building many with conditioning sick associated For air the microbes association who in and that wing. strong involved tower noted members a that authors be cooling revealed staff The possibly in not, 30 could wing. working did tower that by who and ing in members returned working cough staff with questionnaires also dry 69 associated was the and and temporally rate building syndrome, strain attack the building pneu- eye The of sick causes wing between atypical. affected only for was the disease outbreak As in this Legionnaires’ worked Typically, so usual. people, than pneumophila 53. immunocompromised L. higher was more from pneumonia age older, associ- developed average in who was people that monia the 6 Kingdom the and United of immunocompromised the 1 among Only in was occurred studied syndrome[205]. have disease building sick would Legionnaires’ with of likely ated PHM. outbreak than a an level be was higher there to much Interestingly, cause considered a practices be at especially modern could form equipment[203], our it aerosolized medical thus circumstances, in and hunter-gatherers, found certain microbe fountains be Under this showers, can to Legionella as chlorination[204]. and exposure such microbe adequate towers[202], environment, environmental without cooling built the situations water the by of in pneumonia in inhabitant caused infectious places an acute be other of sometimes to type in is discovered a bacteria consider was This to that interesting pneumophila[201]. disease is it Legionnaires’ disease, as chronic known on focus the from Deviating 17 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. uiau oteetn htsm niiul r nwtrdmgdbidns22 rwe okn near working when A. or to buildings[232] have exposed damaged likely water been have not in likely are would individuals not species would some fungal Hunter-gatherers that two extent these populations. the to hunter-gatherer to exposure (IBD). in mayfumigatus disease because high albicans out bowel present C. as point type inflammatory that is al[230] been the of suggest connection et not type also Bacher apparently a PHMHEC They is disease, lungs[231]. The Crohn’s gut studied. the in the adequately from role in not fumigatus similar albicans and A. a C. resolution common the play the very successful cross- eliminating by are a the in generated cross-reactions to helpful for response lungs that response is problematic the Th17 immune that particularly in the (Th17) response reaction be that hypersensitivity of cell is may Th17 17 disease What a type the in helper fumigatus. of found results study T This Aspergillus some The a albicans. fungi, affects framework. causes C. reactive PHMHEC which against albicans the generated Candida into aspergillosis, be fitting intestinal bronchopulmonary to as of seen allergic overgrowth be an acute might that patients, to fibrosis related cystic and research[230] asthma with al’s consistent et PHMHEC is Bacher The species fungal microbes. hypothesis 2 the the PHMHEC involving all of the example part kill cross-reaction important to microbial an as pollution. A likely their air hot of and are so sources fires PHM, are other because including and areas is smoke contribution, all This of microbial effects not microbes[229]. the negative so viable that contain and proposes to homogeneous hypothesis autism[224–226] found not including been well, are has diseases, as smoke wildfires allergic pollution disease[227,228]. from air Alzheimer’s of smoke with including Even rates associated diseases, increased neurological been of have to variety diseases exposure a other mortality[223].and matter of overall and variety particulate visits[221,222] wide fine room A emergency linked the genera infections[220], have new in respiratory asthma[219], 142 changes studies including of were of detection there number including that A event, with found (haze) lead increased also could pollution species study and pharynx[218]. air pathogenic suggested A the microbes severe of been in of a urbanization[217]. proportion has source following the It important with microbiota particularly found associated pharyngeal pollution. a study levels air is recent pollution of less considered. A component air or be on matter um also effects[215,216]. effect 2.5 particulate might pathological negative is PHM fine to a that the the have matter of is the can particulate effect PHM to use potential that of leading Antibiotic the source infection, and actually likely to diseases. confounding susceptibility when One allergic of increased studies[213,214], association the type an some antibiotic this to for in the but leads cause case microbiota, on then underlying the the be which the been may are antibiotics, infections, has PHM for focus these the as need The in that conditions, used be use. allergic are may in antibiotic the be antibiotics it predisposition with of might If a development confounding This cause diseases[213]. the of might disease. allergic in issues which allergic of raise infections, overt development frequent would more the or this the to severe that of children to assume development susceptibility would increased and to This of the infants prior form infections, disease. the allergic occurring of trigger in range effect to observed wide PHM seem a some that to infections is susceptibility the there increase to viruses apply generally also and Herpes might allergy of susceptibility underlie fungal reactivation PHM as and if well Coli So, as E. likely[212]. spp) from include more Mycoplasma infection conditions be (e.g., genitourinary to allergic bacteria Even various appear and and infections[212]. virus) asthma parasitic syncytial with treatment[211]. and respiratory patients antimicrobial rhinovirus, effective in (e.g., after found been reduced viruses infections has is opportunistic sensitization and is of patients allergic tuberculosis interestingly, Examples tuberculosis that And, toll in the forms. increased given multi-drug-resistant be considering of to worth rise seems found the but and speculative highly globally is taking This disease. overt cause 18 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. on nprootts a o enfudi h ri fAzemrsptet n natherosclerotic in and patients Alzheimer’s of diseases[245]. brain other the of and number in a organs found with nearby associated been of been now infection has gingivalis or has and P. instance, plaque[244] infection For periodontitis, allergy. systemic bacterial in than version, in rather severalfound acceptance updated discussed, and increasing are periodontitis, this autoimmunity gained as or has such In dysregulation infections, theory immune oral infection between diseases[242]. focal association chronic the the for of other of recognition occurring, aspects the to were some due least years symptoms recent at resolve where body. of help version the body and updated hypersensitivity of the An bacterial part of decrease other hypersensitivity could part that issue cause another dental in pain. could the infection joint in it of obvious the present resolution infection, no then bacterial were dental was joint, a bacteria a a there was example, same to if there even if related the was that occurred, instance, if allergy was it for bacterial Thus, theory wherever body, of the bacteria the concept of that the of aspect accounts, to followed mid-1900s, One part was ancient and one theory[243]. tooth several early in infection infected the to an focal infection In 1900s of the removal pain[242]. the to the joint connected before whom chronic often in long of patient back resolution a the roots of by its Hippocrates by traces observation popularity theory. actually the gained cases infection including theory that colo- focal some theory infection microbe’s the a least focal to the 1900s: related at The with the is for combined idea of This antigens half accepted as first microbial disease. been rhinosinusitis, chronic the to to chronic has in hypersensitivity contribute and can what that infection aspergillosis to idea or bronchopulmonary nization the similar allergic is is sensitization, above, that fungal discussed hypothesis with PHMHEC asthma the of research of current part and The allergyhistory bacterial and competence, immune infection Focal of article infections. measures to this immune usual susceptibility throughout of the for level discussion by implications and important the detectable have type and be might The imbalance always yet immune not relates suppression/dysregulation. subtle might This immune relatively suppression/dysregulation immunodeficiency. causing a detecting colonization/infection in ability of PHM our difficulties example of in that to above possible Cryptococcus, related is fungi, the it be another to that with might noted infections immunocompetence authors of perceive The rise fun- to the patients[241]. discussing immunocompetent and article among an reactions[239], allergic decades in recent develop allergic raised to was of tendency point types relevant the A several influence exacerbate directly to possibly al- albicans humans[240]. to shown C. in of suggested Interestingly, was could diseases been form mice diseases. exposure has and in the inflammation-related PHM colonization/infection invasion of gut gal this microbial in number the time, and a responses of Over stress to col- defense colonization PHM. physiologic susceptibility albicans by increased in- increased host C. initiated reactions, cause including promote cause thus be hypersensitivity to types, might that dysbiosis, found many inflammation to PHM been that contribute of has to and inflammation dysbiosis [238], exposure grade of low onization be cause Even contributing could reactions. a lergy/hypersensitivity albicans, that C. found incidence[237]. proposes was creased disease diet hypothesis with westernized possible associated a PHMHEC countries, factor multiple bowel The many environmental inflammatory in of ubiquitous disease, studies most issue IBD dysbiosis-related the reviewing the the be and with some recent to groups, And associated a of ethnic Interestingly, only certain frequently dysbiosis was recognized[234,236]. in effects[236]. is of use disease, been as antibiotic negative rate has that use, significant antibiotics increased found antibiotic entirely with cause an review to not associations with always related still dysbiosis be is associated for not might It explanations are do It involved. antibiotics but is overgrow. show sugar/starch hypothesis to type[235], typically high PHMHEC albicans Studies with the C. diet. which those the westernized stated[234]. at allow in the level factors of common deeper what hallmark more a clear a be be is may consumption to there grain found However, refined been and has sugar overgrowth high and albicans diets[233] C. hay. moldy 19 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. oe ies,a namtr odto htue ob osdrdatimn n sascae iha with associated is and autoimmune inflammatory considered that be shows to research used a Epidemiological that are condition tract[256]. There inflammatory respiratory systemic an lacking[255]. and the disease, erythematosus are involve bowel lupus autoantibodies Sarcoidosis often systemic arthritis, known autoimmune. that rheumatoid be but sclerosis, including to diseases diseases, thought autoimmune currently autoimmune molecular of are with number here discussed connections (aka conditions some respiratory has the self-antigens of few a with Only cross-reacting microbes mimicry) diseases. proxies do some are – to least productive that difficult at more biomarkers for Autoimmunity be validated Perhaps be will be PHM. might This might relevant This that species/strains. identifies discovered few that diversity. be a done might total or PHM is to one researchers for research relative only theory[253,254], more hierarchy of PHM until of colonization/infection of context adequately the the diversity for in the looking analysis microbial examine of than of used have scale effects to researchers higher the some need as that or pinpricks.” Just might level be thousand may higher patterns. “a for from also a looking damage it for when of diversity but outlook equivalent contexts, different the a certain from require result in might might harmful This disease particularly microbial and are accumulate, of PHM PHM some many extent that be the may of It understanding analysis? of higher-level lack approaches. for immunotherapy a current Need that and vaccine inhalant hypothesized known bacterial the of be with effectiveness might cross-react the that It limit PHM may might some have immunotherapy reducing colonization least allergen-specific allergens. thus may at current colonization/infection, eliminate dietary vaccines of to bacterial or forms bacterial system reduce immune some using to the that stimulating researchers system speculate be immune might earlier one the the Similarly, of of symptoms. that ability doses by the suggest tolerance small increasing immune would through been oral hypothesis manner[252]. inducing allergens controlled PHMHEC of harmless carefully method The a newer to in the immunotherapy stimulating system ingestion via as allergen-specific allergen immune or defined era, increasing usually extracts[251] current the gradually is allergen the desensitizing it injected In since or as interesting, infections. sublingual is described eliminate era or typically the prevent bacterial of is of to researchers use system by vaccine the immune term for the the strong cases. of was asthma use evidence of blood The in the proportion allergy peripheral that some bacterial of concluded least on work Malling[250] at chemotaxis cited by in very induced to and vaccines review or subjects bacteria contrast A good healthy autologous had in not context[249]. 86.2% but that asthma this that asthmatics bacterial showed bacterial reported non-atopic with was from have study it cells rate to Another mononuclear and success vaccines, considered bacterial high responses. were Klebsiella with a treated aureus, who good were a S. reported asthma They as bacteria, al[248] with asthma. infection the et coli- children allergic implicated the bacterial chronic Oehling 80 They than in treating in important instances. English pneumoniae. in immunotherapy many more in Diplococcus in successful is asthma published and allergy be and bacterial articles pneumoniae to rhinitis that immunotherapy few be allergic concluded bacterial of to the al[247] found cause appeared among et al[246] and example, Bacigaluppi et trials For Nogaller tis. clinical years, several diseases. 50 in several last tested few treating a was in help allergens might least successful bacterial it at to though that some adequate, might desensitization in concept Interestingly, be that present continually related not infections were would PHM extent. of or tooth some ingested the sources infected to being of be an were people understanding that removing to microbes simply no thought be Thus, was were might environments. agents There that infectious partly practitioners organs the probably overzealous diseases. and of was addition, other some It teeth In to theory. removing theory. infection contributing the in evaluate focal be far to the techniques in too molecular interest going current of were of loss lack the the to to led due likely factors of combination A 20 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. a edt oesrosilesta ayalri odto eg,mr netos legctp symptoms, deficiency allergic-type some infections, IgE more Selective to (e.g., research. least condition by allergic at supported many protective be than to illness are serious appears responses more this to previously, allergic ways lead mentioned multiple may IgE-mediated as fact, in hypothesis, In system PHMHEC degree. immune the the to evading According be to hypothesized COPD[270]. and are asthma[270] PHM rhinosinusitis[269], development, chronic arthritis like rheumatoid conditions, precede infections. other to opportunistic in tend observed withstand infections been and repeated has PHM how sig- this that tolerate and such describes methods or has [268] usual eliminate the al cycle avoid, overcome et vicious to eventually Arleevskaya this uses may illnesses, system it diagnosable neuro-immune that effects with the stress-related those and in but pro-inflammatory that nificant healthy PHM. proposes to remain hypothesis related PHMHEC usually symptoms The susceptibility invasion, and signs genetic individuals microbial subclinical proposed lower Those increased some is and/or diseases. have of This inflammation-related factors may other one triggering/exacerbating stress. or autoimmune physiological essentially fewer allergic, and with is chronic psychological to triggering cycle increased lead eventually and and vicious more to infections events This suppression/dysregulation, secondary immune triggering hypersensitivity, invasion, breakdown, stressful cycle. PHM barrier with vicious stress-related combined and genetically a in not microbiota possibly to occurs did with, factors, humans lead coevolve that did These infections, humans chemicals that and microbes individuals. microbes of reduction to susceptible the exposure with coinciding repeated agents with, hypothesis, infectious coevolve PHMHEC other the multiple to to According susceptibility or increase Dysregulation autoimmunity. could issues to causation[266]. PHM causation contribute disease agents by other autoimmune thus disease infectious system that explaining and autoimmune multiple immune in conclude other of the difficulties involvement to and of the simultaneous least, of suppression this of The very some of cross-reactions for the al[266,267]. complexities of account et at The could importance Root-Bernstein or the by well. disease, downplay discussed as autoimmune to are involved of reason be cause a must a factors as as protists. or seen self-antigens cross-reactivity animals with been bacterial plants, they microbes same has high be the cross-reactivity hosts, adaptive from the frequent multicellular be evolved sequences larger, could This consideration, life their proteins bacterial inside all host further survive and with that to On cross-reactivity fact proteins attempting enhance the microbes to human mutations for considering bacteria. addition, between bacterial expected In of from similarity been ancestors. exempt have species of unicellular is might protein degree 40 self-proteins human human high only “No with the paper, at al’s[265] of found looking et cause they Trost by microbial and of usual[264]. And a title reasons than recognize the autoimmunity non-pathological consider to motifs.” of and to level be Autoimmunity interesting pathological higher may means is a key of It a causation. to the variety as leading disease Instead, controls a be in healthy for may well[263,264]. in factors that as occurs even inflammation underlying functions and that to other infections[263] damage serves during respect after phenomenon possibly with natural up” issue a “cleaning component key be of autoimmune to the strong found a be been has not condition has a may whether rhinosinusi- not hypothesis, chronic PHMHEC or asthma[259], the respiratory of as chronic perspective such the of autoimmune, From COPD[262]. number be and a to fibrosis[261] in pulmonary considered found diseases. idiopathic traditionally been autoimmune tis[260], not has some autoimmunity are least microbes of that at autoimmune inhaled degree diseases in and between some PHM for conditions connection inhaled evidence respiratory for a Interestingly, role between supporting a connections evidence with above damp the compatible the as is to such And diseases environments, adds microbe-rich diseases. This with non-respiratory previously, associated agriculture. and discussed commonly as in be And or to diseases[258]. known buildings airway are by diseases preceded airway often many is diseases[257], autoimmune of number 21 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. h7rsoss hte rntoeo hs he eprcl epne oiaei eemndb many by determined is and dominate (Th1) responses cell cell 1 the helper type colonizing T helper already three T these downregulate microbes to of (the responses one sink Th2 not the for or in tendency cells system Whether the already the immune mast as water responses. address The antibodies, seen Th17 To the be other threats. of might on. incoming and instead This left countering IgE on for been body). involving being important has responses faucet are faucet Th2 the world. responses the the the prioritizes enter rapid external senses uses to These system the continuing system environmental immune eosinophils. are immune with as the and and the seen interfaces analogy, threat of on, be have continued the analogy might being a of that on are the faucet context body left microbes by the human external being In illustrated that faucet the body. sense be The of can might on. system surfaces elimination immune left at avoid The being encountered might faucet being PHM a to some microbes due how overflowing viewing sink Th17 the of and way Th1 simple inner-directed A reduces response immune response Th2 target immune outer-directed to – system immune analogy the Faucet of ability the influence component[276]. may subdominant the virus target one to virus[277]. system how immune another so discussed the substance has approach allow a research will an to related this to bound and Other is led recognized component has immune be immunodominant won’t This the the it where keeps components. that vaccine considered virus subdominant influenza immune universal are conserved influenza ineffective a widespread the that developing essentially more to of antigens and on (epitope) certain lower focusing component to much from immunodominant body. a responds system the the in system instance, inside result immune For PHM ones the the response. subdominant where of the other situation antigens to while microbes different the difficult immunodominant, environmental according the to more reaction-provoking target similar camouflaging, effectively the it is the more to This make removing can exposure of could system the immune method that reduce the One camouflage to that so of tissues/organs. be colonized. more would already type or have hypothesis, one a in PHMHEC that provide living those to could target adapted adaptive mucosal microbes already to large of at those variety environmental a encountered to large antigens identical, the for a microbial not fill potential Thus, environmental but to diverse be similar, microbes situation, would be of this would diversification there In a surfaces body, describe roles. human the to or the biology enhance niches evolutionary in ecological can in colonize used itself, term to by a areas variation, radiation, different microbes antigenic system[275]. many environmental This immune so as the With body. occur evade human would to variation the microbes antigenic within the that of habitats ability expected diverse encountered the be microbes would to related It closely adapt the by environment. camouflaged the being PHM, as in viewed some be particular, might PHM in Colonizing/infecting and, immunodominance microbes, and which variation by –antigenic ways Camouflage other below. the discussed of adaptations are multiple few system previously, has described immune a as often the and cells, strain suppress/dysregulate adaptations; within survival microbial might of allowing single factors set is a virulence one and use” contexts, are “Dual defense, certain of defenses. in host lines counter many but that has the helpful, system afforded in be immune protection microbes The can Thus, era pathogenic. responses post-hunter-gather become westernization. hypersensitivity the can immune with and control other associated inadequate and and exposures to IgE-mediated increasing respond humans by that rapidly optimally answer: of to an are context ability suggests why hypothesis current the then PHMHEC evolve proposes, The not hypothesis decades? PHMHEC the recent did in the not prevalent as more are protective, diseases are these reactions responses cause. IgE-mediated allergy/hypersensitivity the the the to If response that a suggests but This disease, of disease[89,271–274]). cause autoimmune and cancer 22 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. oista aesmlrt nsrcuet aiu rg,wihmgthv mlctosfrtreatment. for produce implications that have microbes might which of discovery drugs, various the to to structure lead cross-reactions in might medication similarity It have to have investigating. that D related worth toxins vitamin being seems against antigens reactions antibodies microbial allergy/hypersensitivity fact, with diseases[286]. medication in autoimmune for And certain potential D. with in The vitamin substances level like other higher with VDR, a an cross-reaction the this autoimmune at produce a bind blocks found in might be also been system would product blockade that immune there microbial structure receptor the and similar a cases, toxin, D a VDR-binding some that Vitamin the in hypothesized to that proposed response been speculate the immune might has One is it pathway. effect immune previously, PHM important mentioned toxic other low As including a the its possibly of However, disease[177,181]. factors, to example other agriculture[285]. to disproportionate possible of found secondary effect Another been beginning be has the might an it disease since have because cause plaque PHM to to oral a ability exposures. able be in its to DNA in is considered ancient rise be and recent from might levels levels It increased low manipulation. (e.g., immune at at its diseases to present respiratory due typically abundance of is number gingivalis a (cardiovascularP. diseases including other arthritis[78]), many with rheumatoid COPD[282–284]). associated asthma, disease, been manipulating by has Alzheimer’s periodontitis disease to disease, Periodontal leads apparently system[281]. pathogens, immune oral the other several with interacting in gingivalis, P. system overgrowth immune albicans lung. the C. the manipulate the in that since response Toxins immune inflammation, the the tract affect of intestinal negatively nature the to An pathology[230]. in systemic appears lung response the gut to response. contributed Th17 the reinforces apparently immune induced lungs, also the the albicans in example misdirect C. fumigatus This A. might a with where another cross-reaction previously, a one with discussed combined with was cross-react this of that example antigens have cross-reactions that to Microbes the related of help response model would immune And mouse that of a responses hypothesis. Misdirection response[279]. using PHMHEC rapid study Th2 the IgE-mediated recent to a include a according toward responses to microbes response invading Th2 according against the response dermatitis[280]. protect biases Th2 atopic a stress disease, potentiate system that skin to immune idea the appears reactions. by the also allergy/hypersensitivity perceived supports obesity be Th2 to stronger also likely response. to research be Th2 lead would a Recent might antigens toward this PHM tendency the and the elucidated[278] of increases foreign, fully that some foreign more showing least not more research as at it still discusses that makes Bretscher[278], is seem that by would antigen reactions topic It an the Th2 to of vs component review a a Th1 Interestingly, adding determines complex. what clearly is in tolerated and involved and be mechanisms could range exact potentially moderate The threshold more certain a the a within needed, below kept symptoms. longer exposures are no noticeable maintained, is exposures without or focus are If reduce external defenses help the decline. barrier Once to to mucosal needed likely body. be the is may colonizing hypersensitivity avoidance, that already antigen Th2-mediated mechanisms microbes through non-Th2 the instance, the of for of many increase eliminated, cells. eliminate production presumably or Th their can reduced other system is is immune of cells threat the that Th antigen microbial decrease of external feature and the recognized differentiation Once a own But their promote cytokines. can of number that a cytokines of levels including factors, 23 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. icsino oedsae ffcigtegsritsia rc sa prpit rlmnr oasre of survey a to preliminary appropriate a an Thus, is diseases. [293–295]. tract inflammation-related diseases gastrointestinal and these autoimmune the of additional and affecting nature some autoimmune of diseases systemic allergic, some the phenomenon and support of this imbalances to discussion inflammation[78]. microbiota tends describes oral also gut review diseases of between inflammation-related case recent would relationship neuro- the also (i.e., recognized A spread in but body increasingly effects supply, to the The systemic locations. throughout blood microbes to occur distal the leading for that and at potentially effects tendency system factors effects system lymphatic multiple the nervous including the and from via system cross-talk), arise immune and immune to cell, to due to expected expected cell be be e.g., body, would a the only throughout throughout processes not disease interconnectedness evolving This additional the and influence environmental responses to and inflammatory immune predicted stress of or of like lifetime. be Many factors autoimmune pattern would other changing allergic, with exposures insomnia. along The of clear chemical/pollutant and infections, levels a opportunistic changes later. and of increased develop exposures/invasion mood diagnosis PHM might itching, headaches, precede sometimes or moderate would but menstrual rashes to likely condition, or occasional mild manifestations premenstrual occasional fluctuations), milder mild bites, the mood meals, insect and milder after after diarrhea, of itching rhinitis Examples pain, clearer. would symptoms, (e.g., and that bowel extensive connections symptoms more the occasional included, become are might organism include diagnosis hypothesis (the manifestations a disease holobiont to holobiont lead entire united not a the do support of typically that scale manifestations worth the milder lower is Once on It and supported upper section. earlier between be an overlap microbiota). might in was its unity discussed there and as similar that hypothesis, a found disease was airway whether hypothesis. united it considering disease the diseases, holobiont to airway united leading and on a diseases, research envision airway genetic might of multiple one years on the hypothesis, the disease individual, depend Over airway an would united in the diagnoses exposures. if to first PHM comorbid Analogous appears expected of of that pattern be addition disease the would the The including and what PHM. factors, environmental disease widespread is many that diseases of of inflammatory rhinosinusitis role progression important chronic and an in autoimmune was sinuses allergic, there the of from colitis[292]. interconnectedness ulcerative microbes The in implicated and factor rhinosinusitis has disease etiologic chronic reflux study an including instance, gastroesophageal interesting as For body, headaches, patients An anxiety, the premorbid system. of more apnea[291]. gastrointestinal experience systems sleep the to many and reported involving system are conditions patients nervous between autonomic connections brain, interesting the also are chronic and There environmental indicate polyposis, well. rates nasal Marple[290] disease as media, increasing order[289]. involved otitis the however same are asthma, involved, factors the as likely such are in factors always disorders Genetic and not e.g., rhinosinusitis. allergy, rhinitis other, allergic food the between after and condition links asthma allergic noted of one rhinitis, develop chance allergic children which dermatitis, higher in atopic discussed a frequently acquired [288]. is have even increasing march allergic has diseases is The diseases and autoimmune autoimmune mentioned syndrome more certain are autoimmune or these but multiple with of three name here, Many Having people the completely onset. disease[287]. instance, cover disease autoimmune For precede to another that developing extensive conditions article. increased too medical finds this is as one disease, well throughout connections inflammation-related as any these comorbidities virtually of for studies one risk different subject if among that The connections indicates more research found. the published studied, being are are diseases inflammatory diseases and autoimmune allergic, united more the The – diseases inflammatory hypothesis and disease autoimmune holobiont allergic, of nature Systemic 24 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. obebidrnoie otoldtilo ititreto n5 dlswt rial oe syndrome[318]. bowel irritable a with in adults of 58 benefit in type significant intervention statistically diet this a a for of shown trial has support controlled test randomized is hypersensitivity blind there double food needed. and non-IgE-mediated IgG, of are IBS[304], involving type studies of tests Another more specific treatment hypersensitivity However, on successful food conditions[313,316,317]. based to that other rather tests led shown in trials of have approach controlled tests, assessment randomized studies specific base well-conducted Some IgG4 to of including preferable mechanisms. results appear the about would on theories markers it than bowel immunological evidence, inflammatory other atopic above in and in the reactions IgG4 not of food light but IgG4-mediated the disorders, of In airway role upper the correlate esophagitis[314,315]. and for to eosinophilic asthma of appeared evidence and in levels some is disease[308,313] IgG4 inhalants there antibodies[310], that to showed And IgG4 of hypersensitivity study recent with IgG4-related dermatitis[312]. role and a called the associated levels addition, diseases of IgE is In of understanding class with antigens[311]. inflammation in a thorough food chronic least of bind a at diseases, incidence can of reassessed, increasing which IgG4-related the lack be In and to the system needs given reactions[306]. immune diseases. view true that the food this in proposed especially assess that antibodies to is been suggests IgG4 means has This areas a of it as diseases[304,308]. variety and used a certain IgE-mediated to antibodies, in be have specific evidence “blocking” not who antibodies increasing should called However, and patients IgG4 been been tolerance have have high desensitize with antibodies they on to associated IgG4 result, based are conducted specific a Tests they immunotherapy in As increases of antibody. disorders. because IgG success partly allergic produced the least cell at with criticized B correlated been the have of foods particular subtype particular of for a types specific has levels is new that ) IgG4 revealing type (IgG all the are G is for immunoglobulin tests reaction elevated test new food to to adverse related and need non-IgE-mediated foods. being involved, would a possibly non-immunological not not of one as does example were be investigated since reaction One been they cases, to a below. many that that assumed discussed in show Proving as been difficult reactions, to assumption. often extremely reactions that have be verify immune to could that possible done system reactions been immune typically food the not involve adverse have tests of condition syndrome[309]. though types severe even enterocolitis other often protein-induced an food are called including There children there conditions, However, small hypersensitivity tests. and blood non-IgE-food infants specific affecting several IgE mainly are or of that tests recognition reactions prick all skin now virtually by include shown is to as other used reactions as with been immediate well has IgE-mediated as associations intolerance not research[306,307] food IBS, IBS term in the with area Historically, controversial patients found. a conditions[308]. of reac- are been tests have allergic subsets hypersensitivity intolerances[305] in In food Non-IgE-mediated food important patients[302]. and are hypersensitivities[304] IBS which food cells, in allergies[303], mast tract increased food gastrointestinal approaches. of the treatment finding in new have the tions, developing advances include in unknown, advances diseases[299], and interesting is allergic involved Some cause mechanisms as with such the underlying association conditions, understanding its in other in Although constipation, decades with made and/or conjunction recent been syndrome[301]. diarrhea in in fibromyalgia pain, occurs countries and commonly abdominal many ME/CFS[300] self- IBS as in showed such bloating. these increasing symptoms study and of be gas includes recent 56.3% typically to with a It 68.6%, reported addition, at been westernization[298]. In population month[297]. has European per incidence studied[296]. a days IBS in population 3 studies symptoms least the some bowel at of with of symptoms (IBS), 22% degree reporting syndrome some as individuals bowel least high irritable at as of of incidence be reports the to of it estimates reactions their showing food in varied for have tests Studies treatments, pathogenesis, syndrome: disease bowel bowel Irritable inflammatory and syndrome bowel irritable diseases: Gastrointestinal 25 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. sfrhreiec htrlac nayoetp fts,lk g pcfi lo et rsi rc et,is tests, prick skin or tests blood specific it IgE And like test, contexts. of genetic type and one exposures any microbial on diverse reliance hypersensitivity with of that types association evidence many that in further in to hypothesis is expected PHMHEC apply the the be on to also would based related might are diets reactions progression tests from of benefits this types showing different that and of mechanisms be results hypersensitivity might diseases. different it implicating other studies then perhaps These true, and IgG4 pro-inflammatory is diseases a that this IgG4-related to If speculated of lead that might development and noted individuals. eventually the immunotherapy but allergic al[314] It disease, oral some et IgE-mediated in Wright during reduce cells. state develop to esophagitis. mast produced to PHM eosinophilic be esophageal known initially to in as might been related research way has be recent same esophagitis might from the eosinophilic esophagus arise the in might in respond insights And response Further not cell disease[328]. do mast this cells in in esophagus. involved mast difference the be the skin colonizing/infecting to that that food- appear hypothesized found of not be importance does cases been might the IgE also some showing esophagus[314,315]. esophagitis, has in the eosinophilic it mechanisms in in used levels elucidating being IgG4 in now specific promise are measurements methods shows on testing of challenges based Specialized type rhinitis[327]. assessment allergen one nonallergic reaction that nasal be allergic found to and al[325] has local thought levels test Interestingly, et previously activation Savage IgE basophil useful[326]. by The local be study cells. of A to of an mast shown types than reactions. reaction diverse rather relevant been of that basophils the also involved showing type all peanuts thus to find this found, reaction to being called IgE-mediated needed are study be mechanisms 80% recent may reaction least allergic tests a at typical of showed of patients variations authors 4-fold Other the The a IgE[324].” of having involving (allergic), 68% not disorders. atopic reaction results, atopic typically allergic test were of “atypical the test prevalence this on degranulation[323]. in not using based eosinophil did reactions increase diet involve patients showed elimination IBS that did many Patients an apparently in improvement. on but foods to months reactions, to molecule. due 6 reactions larger cell-mediated typically that a After mast are showed to typical (CLE), bind they with endoscopy the to occur, laser ability involve individuals chemicals confocal their typically of to using from study resulting particularly reactions not number antigenicity A immune was their do the When additives with controls T1D, haptens, food results. Healthy being in and LRA chemicals blood Interestingly, LRA. chemicals the frequently the of environmental the to most levels testing[322]. minerals, according to the promising toxic high LRA was according showed to with dairy T2D T2D) hypersensitivities reactions Cow similar with and immune A food (T1D patients T2D[322]. any mellitus in for significance[321]. show diabetes reaction significance statistical 2 statistical food reach type reached identified not and which did a I reduction, with results type sugar combined syndrome the fibromyalgia both when in although and in symptoms controls, diets, other approach several individualized to LRA and to the pain compared improve led called to patients is testing found chemicals was of and program, results foods repletion A The nutrient to amyloid reactions assay). hypersensitivity serum response non-IgE-mediated index, on (lymphocyte based mass focuses diet that body The test improved test. A placebo significantly the the scores. with to and according questionnaire associated group test to symptom ALCAT treatment was sensitive medical the The not results to were and adults. test they according 46 ALCAT that to of diet the sensitive their group were on from placebo they removed a that foods to diet had included them their group trial compared from The removed and symptoms[320]. randomized group foods blind medical treatment had double and 4-week the inflammation a in index, in adults tested mass also 87 body release was intervention assessed DNA dietary that a eosinophil trial A shape controlled implicated to results reduction. and ALCAT of symptom reactions use pathways[319]. with the The signaling of associated C mechanism kinase be the protein to with elucidate intervention. found associated diet to was the attempted concentrations determine study elastase to used later neutrophil were in results (ALCAT) reduction test A activation cellular leukocyte antigen The 26 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. szdt edt h nit,wihotnocr ihdpeso,adteicesdssetblt othe to susceptibility increased the and depression, with hypoth- occurs are antigens often PHM-associated which Th2 anxiety, the to and reactions the anxiety the to of Thus, lead symptom colonization/infection to stress-related gastroenteritis. PHM the esized the prior both before since for hypothesis occurring account response[338]. PHMHEC skewing anxi- immune potentially the skewed greater by could Th2 have explained a hypersensitivity to showed be likely and also more could they were and results and IBS episode, study Salmonella gastroenteritis post-infectious These acute of Campylobacter, developed A number the who as significant before IBS. persons such a scores to that ety in bacteria found related occur from depres- was to be gastroenteritis It found gastroenteritis, to infectious is Shigella. infectious found IBS acute between Post-infectious have been interactions IBS[337]. who also significant of individuals have risk found infections subsequent personnel and and anxiety military stress well. sion, in here, as IBS PHM discussed of reduce diseases the on study FODMAP directly of other based low may some in antigens least and a of as at antigens on Reduction Just reduce PHM-produced are could symptoms. the who it reduce with patients because to cross-react partly in help that helpful reduced could antigens be be this might and likely methods antibiotics, would testing the taking tract allergy/hypersensitivity by are intestinal mediated who the or be in diet could PHM activation some to immune least this At precursor the that showed necessary in concluded study state a authors pro-inflammatory recent a microbiota[336]. be the A with gut and even motility. associated system, some intestinal are perhaps nervous least IBS, abnormal and central include with At the which response reinfection underlie treatments. disorders, immune to antibiotic gastrointestinal repeated functional thought repeated Th2 and/or continued production need antibiotic-resistant upregulated The SIBO autoantibody be an with the inhalants. might patients cause and that some might food why PHM PHM in explain the antigens also of cross-reacting could their proportion PHM and colonization/infection a PHM PHM autoanti- of of for higher to level explain, presence higher The exposure a could above. greater from It mentioned result a SIBO. could autoantibodies and patients and/or the treatment-resistant IBS more of of the levels features in or higher unknown[333,335]. many bodies have Whether still explain patients to is some low. potential why SIBO levels the instance, of bacterial has cause intestinal hypothesis underlying PHMHEC small complex true The motor the the migrating keep involved, the are helps affect for autoantibodies and mechanism to the a motility thought is not intestinal are gastroenteritis autoantibodies normal low acute These of causes the helpful[333]. types support[334]. that be certain like gaining of to is growth, result appear that a Polyols) bacterial also SIBO as and antibiotics self-tissue fuel against Certain Mono-saccharides that produced Di-, support[329,331,332]. 78% Antibodies foods have to Oligo-, diet, Fermentable the 4 elemental in (low reduce an occurs FODMAP and that which low diet approaches (SIBO), or other overgrowth Dietary IBS carbohydrate or bacterial Some intestinal fermentable itself patients[330]. discussed. small gluten is of IBS of PHM that result of of is abundance. a later. source topic discussed be in potential interesting be may increase a Another will which as least might as gluten, at fat to foods[305], PHM consuming for diet, gluten-containing expected when opportunity on some PHM of symptoms more be section characteristics contain least give more later would might would have at a that tea, that also In so and items patients ingredients increase. coffee harvest, novel all to alcohol, after PHM of like foods, some beverages, long number spicy make carbonated consumed a to and limiting contain often used fatty Fermentation or beverages are as avoiding Carbonated spices well include PHM. and as in recommendations[329] newer coffee high dietary the and evaluating be IBS tea studies current alcohol, further that However, beverages, needed. interesting are diseases. is diseases disease other of elucidating It variety many and in a in methods promise in but testing shows tests novel antigens IBS, of multiple and in types of mechanisms only availability of The not diversity on available. mechanisms, the reliance previously from of tests resulted understanding of probably increasing has types reactions limited allergy/hypersensitivity more of the role may the mechanisms of hypersensitivity underappreciation patient. Multiple An same the reactions. in allergy/hypersensitivity involved food be even out rule to inadequate 27 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. etoiga oelpsnrm. lhuhti sntagnrlyacpe da icsino this of even discussion IBS, to with a appear continuum idea, diseases a Both accepted on diseases. generally lies the a IBD between that not similarities many proposed is highlights been this it has Although because it interesting al[349], is syndrome.” concept et “overlap Rani an by mentioning article due cross-reacting recent occurring to response a the exposures defense In host And dietary strong PHM. and a environmental be of with could concept combined microbiota the antigens. potential when new by of colonization/infection replaced the list PHM be that might to a constitutes proposes tolerance what in hypothesis impaired discussing PHMHEC included of explicitly The idea colitis, without the ulcerative microbiota. microbiota,” to of new new to cause according the tolerance the disease Enterobacteri- “impaired discussing the responses the when pathogenic of inflammation. to increases al[348], chronic leads observed during et overgrow usually what Roberts-Thomson that the be pathogens by might followed opportunistic known be PHM including then abundance aceae, might Crohn’s low This observed[343]. in involving also hypothesis. implicated is dysbiosis PHMHEC been effects Mycobac- of anti-inflammatory have as type with such spp, bacteria, associated A Listeria and species IBD, and of in diseases[137,347]. spp reduction role inflammatory Yersinia a A other play paratuberculosis, disease. to of thought number subspecies are a avian Coli and E. terium invasive asthma particular, Enterobacteriaceae adherent in in of as tract Proteobacteria, such level intestinal Microbes The increased diversity the dysbiosis. An in microbial of noted of bacteria. type been levels pathogenic common also lower many one has include and is Enterobacteriaceae, that Proteobacteria family and oxygen-tolerant IBD, the of in dysbiosis abundance observed as reflected greater typically be well are a often as case, relatively would which different any many dysbiosis PHM, mean In of the to hypothesis; dysbiosis. from degrees used PHMHEC effect of being of and the degree level its with some types some consistent to in have of due still be variety might late would individuals wide controls of asymptomatic healthy criticized being A seemingly dysbiosis been of in has situations[346]. degrees present dysbiosis or different term types in different the to indicate of things due would use largely This The likely is controls[345]. develop- disease. discussed. dysbiosis healthy the the regarding of to of conflict that prior conflicting apparent onset just to This be the non-affected that close to after their found was appear began and disease microbiota would dysbiosis patients Crohn’s gut first the of both the at that onset in disease, what the observed Crohn’s In detecting been of on illness. has ment focusing the it study precede and another may IBD microbiota[343]. data, dysbiosis in intestinal So, role to a members[344]. responses play family immune to autoimmune, abnormal thought be from is to result considered Dysbiosis to previously of asso- were hypothesized inflammation in They worldwide are involve increasing diet[237,342]. they both are westernized now and both a however, but IBD, of respects, of adoption of number the types a with common in ciation differ most They the tract. are gastrointestinal colitis the ulcerative colitis and ulcerative disease and Crohn’s disease three Crohn’s the from disease: stemming bowel the potentially Inflammatory with hypersensitivity. be as compatible and well seen is stress might heterogeneous are colonization/infection, interventions one as causes PHM Helpful IBS with of treatable of components multiple causes, entity[304]. view PHM-related the clinical This treatable since a multiple neglected. hypothesis, as are and PHMHEC causes IBS agents[341] treatable of some infectious these existence if in of overlooked the symptoms role questioning PHMHEC disease the even the emphasized to author of have contributing perspective detected authors infection the been From Some opportunistic has patients[339,340]. secondary which IBS a trachomatis, some Chlamydia be of patients. bacteria, intestines could small the this the is hypothesis, in IBS levels to low linked at agent infectious Another IBS. and gastroenteritis 28 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. hsatce oee,a ilb umrzdblw o ayo h ottoogl tde diseases studied thoroughly most the of many of for scope below, the beyond summarized is be diseases will disease, inflammation-related as and celiac However, autoimmune diverse disease, article. many the this heart all rheumatic of Discussion sclerosis, lateral amyotrophic spondyloarthritis sclerosis, diseases Multiple FMT related from and infection inflammatory an to autoimmune, due Other death efficacy a recently, and concern safety and, is Long-term conditions, these there supervision. for however, medical reported[359]. established conditions without been promise; different themselves, been has many showing it not in in do has is studied reduction to FMT and being with trying of would is combined autism[358]) are FMT it were people and effective. FMT addition, some more IBS[357], if that In be Perhaps disease[356], would lining. it Crohn’s likely diet. PHM mucosal and and (e.g., not of the antigens environment sources would invaded two the exacerbating it have latter in the However, the may repeated exposure lower that be PHM remission. likely infections change to this to not would opportunistic hypothesis, has leading and PHMHEC microbiota generally microbes, the PHM fecal but of anti-inflammatory affect colitis the view more ulcerative changing of increase in point since more potentially the helpful however, expected From be dificile)[354]; maintained[355]. be to be Clostridium generally might appears to (formerly is improvement also It infection for FMT (FMT). dificile regularly transplantation Clostridioides needed. spp. involve microbiota in Listeria is and fecal effective and research complex is spp be during more Yersinia studied lifestyles to just be being in found not may currently and and approach causation system products interesting the refrigerated food An so just the not widespread, in sources, becoming occurring diverse suggested was were from this changes refrigeration PHM of cause other when the addition, of era use part In the the be cold also of refrigeration. the may species beginning to supporting unknown link the other thus that of incidence, suggests hypothesis timing disease PHMHEC the Crohn’s The Crohn’s on increasing in observations with the found made coincided that often al[353] it hypothesis. are noted et chain found spp, was 20 Forbes and Listeria the It by and refrigeration in study spp of disease 2003[352]. Yersinia A Crohn’s as in of such lesions. diseases outbreak environments, disease hypothesis. the refrigerated Crohn’s PHMHEC paralleled in explain the chain) survive of to cold that discussion (the proposed this refrigeration was to of relevant immune hypothesis use is earlier, chain disease mentioned well. may cold Crohn’s as involved as explain The And effectiveness microbes to antibiotic occur. proposed the conflict- lower may hypothesis of to is reinfection A some lead thus, might evidence hypothesis, significantly and PHM this affected food, the the would be to or antibiotics from IBD, not environment according and suppression/dysregulation may involved, the addition, in PHM be in In potentially present the antibiotics could of be them. protozoa from some against and least ineffective viruses benefit at fungi, be because modest Archaea, partly antibiotics. some be the by might be this to And ing[350,351]. appears to there hypersensitivity reactions Although from immune increasing response to immune microbes, contributing frequently, commensal inflammatory upregulated more including them. an The barrier microbes, mucosal against many of intestinal PHM. Thus, The the result of permeability. cross likely intestinal the abundance would individuals. greater be and cause or increased susceptible also could barriers, IBS could the genetically microbes PHM mucosal from to in commensal develop across due known occur can translocation/invasion to response might IBD their response pathogens, that with immune plausible opportunistic observed PHM, been seems of have in it antibiotics increase Increases and hypothesis, subsequent diets discussed PHMHEC elimination dysbiosis. as the to dysbiosis of subclinical responses and perspective positive diet the IBD, article. westernized From and this a in IBS infections, elsewhere in stress, discussed And as as observed, al[349]. such et factors, Rani same in the of many involve 29 th etr.Bacteria century. Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. ies ntels 0yashsbe rpsdt erltdt nrae i olto[7–7]and/or pollution[375–378] air increased insulin-producing to the related which be in to diabetes, proposed 1 type been example, many has autoimmune For of years and exacerbations allergic exposures[379,380]. 50 or of chemical last incidence environmental incidence the in increased PHMHEC in The implicated the a disease been diseases[162,375,376]. of with have result autoimmune consistent environments a including as as microbe-rich diseases, seen increases and that cross-reaction be pollution pathogen this might Air opportunistic If it an and/or an disease, system. food[374]. PHM immune be celiac a refrigerated suppressed/dysregulated also in be in PHM-induced stain- could involved can survive surfaces, fluorescens causally but plant P. can on be symptoms, and hypothesis. and to walls causing buildings confirmed and without moldy human showerheads in is body the found surfaces, in the peptides been steel found of has antigenic be less fluorescens areas can and P. that other epitopes pathogen[374]. bacteria and to opportunistic environmental gliadin lungs an reaction between is tract, the cross-reaction fluorescens gastrointestinal and P. a agents fluorescens. found Pseudomonas infectious study[373] from more recent or a hypoth- one they Interestingly, PHMHEC when to The potential recover responses are factors. patients cross-reactions immunological missing celiac PHM more to gluten/gliadin. all and/or or leading suppression/dysregulation not one immune factors that of PHM missing existence fact and that the the dysbiosis suggest to and intestinal would point review[372]. esis disease of also recent celiac role gluten a The of eliminate in strictly nature discussed States[371]. to are systemic United found predisposition, frequent the genetic been The requisite have in be the disorders patients to with allergic disease suggested along and celiac been factors, autoimmune implicated has in environmental Other been overgrowth common have bacterial patients[370]. more intestinal bacteria disease Small be rod-shaped celiac enterovirus[368] disease[369]. certain some celiac and Also, in of involved virus[367] factors. outbreak Epstein-Barr Swedish triggering a reovirus[366], possible in as with suggested infection been asymptomatic have with disease, infections to celiac predispose In could which pathogens. involved, suggest opportunistic PHM would Strepto- hypothesis infecting of PHMHEC to or number The addition colonizing a multiple in disease. likely heart microbe, are rheumatic infecting there explain additional understood[365]. to that one needed partially least be only gluten tissue at may pyogenes, how and and heart coccus discussed complex antigens has with is microbial al[266] pathogenesis cross-react between et the cross-reactions Root-Bernstein antigens however, disease, bacterial below), celiac In (see streptococcal in support And that cross-reactions. some involve have believed damage[364]. promising to heart is a proposed to it be leading been to disease, have appears heart diseases this autoimmune rheumatic needed, several are cross-reactions, studies significant Regarding borderline more a of Although found bacteria effectiveness and patients. and research. the controls fungi the of to that the line in compared suggested in patients Aspergillus been differences arthritis in found rheumatoid has increase of al[20] it fluid et and synovial Hammad the reported, evidence assessed[76]. lesions. in autopsy been be brain brain has should sclerosis, in bacteria therapy lateral found as amyotrophic anti-microbial and differences In microbes fungi significant patients. of found both epilepsy and set implicating patients from diverse sclerosis found samples multiple al[25] a similar living et to by microbial of Kriesel compared specimens triggered between biopsy tissue. differences is brain autopsy significant sclerosis analyzed brain detected They multiple in al[77] controls that et to suggesting relative Alonso evidence patients and increas- sclerosis al[23] is multiple diseases et in in autoimmune/inflammatory Branton communities implicated in tissues found. been affected being have the ingly Microbes in exac- communities and microbial disease[361]. microbiota[293]. initiation in autoimmune gut Differences the the of with in development associated changes responses, the be including stress to to ways[362,363], accompanies found multiple predispose often been which to Al- has disturbance, found Stress areas. Sleep relevant is cells. discussed diseases[109,349,360]. the as mast autoimmune all diseases on of autoimmune in section in erbation hypothesis later found PHMHEC being a the increasingly in is with further inhalants compatible and generally foods to be lergy/hypersensitivity to appear findings the 30 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. n hsvraiiyi oetal eae oterl fsrs sdsusderir nsm tde,exposure studies, some In earlier. discussed as stress of are role there the which to groups[403], in control related of condition potentially members than is variability a variability rate heart mastocytosis[402], this lower have and with to shown patients organs. were multiple individuals in reported ASD in Affected been higher cells has 10-fold mast It anxiety/fear[401]. hypersensitive is as of such ASD numbers ASD, of autoimmune increased of Mast symptoms with rate the obesity[398]. found the of and some that been with hypothesis. have conditions[400] connected PHMHEC been associations allergic the have cells and with inflammation[399], compatible involved[398], are maternal are that inflammation diseases/autoantibodies[399], features ASD contribution, brain revealing genetic and is a Peripheral research a ASD is to years, there recent leads component[396,397]. Although In environmental that interaction. significant disorder social a neurodevelopmental with also common is difficulty increasingly there including an symptoms, is of (ASD) variety disorder spectrum westernizedAutism a with disorder spondyloarthritis spectrum of Autism association hypothesis. an PHMHEC the supports acute with data consistent periodic is Limited with which stress[395], PHM. reactions along and hypersensitivity the allergy/hypersensitivity[317,394] infection, diet[393], and of chronic proposed suppression/dysregulation underlying effects the immune The the that from infection. increased from suggest result to polymicrobial would bacteria, might due hypothesis a infections as be PHMHEC of to exacerbating such The part hypothesized fungi. stimuli, be are causal may that inflammatory proposed exacerbations fungi varied for the disease unknown to to periodic hypothesis an reactions in Exposures with Catterall-King immune result infection transmitted. the fungi, chronic other a sexually of and for version primarily viruses role updated causal is and a an that proposes serious life[391]. is fungi It the of diseases[392]. infection to related aspects fungal and other add to spondyloarthritis many significantly involvement related and fungal could health hypothesis Increasing temperatures on Another burning scale. having warmer global from is from a change dioxide result on climate carbon might effects occurring atmospheric westernization increasing that increased of disease effect The chronic another temperatures. warming.in yet global disease warming to is to related to leading fuels be colonization/infection related fossil to fungal appears greater be that of might infection. emergence instances a pathogen facilitating undetected that of fungal other thus a toleration be body, of toward could human case there fungi first the However, the the of be of temperature to evolution new appears the driving This a to of temperatures closer to emergence warming is hypothesized the of which is in result temperature, It implicated the continents[390]. higher been partly, three has least on which at separately warming, be, global and treat simultaneously of to pathogen role medication the fungal anti-fungal They drug-resistant consider of al[388]. to use Benito-Le´on interesting et successful is by the It discussed of is report diseases patients[389]. a sclerosis other including multiple and are evidence, several sclerosis of results multiple lines These multiple in discuss role pathogens. fungal possible opportunistic infections. system, A immune and opportunistic the multiple PHM suppressing/dysregulating to PHM multiple susceptibility might westernization-related reducing to antibiotics of leading not role The to mi- causal involved. other did due a agents implicating with who benefit research multiple infectious compatible patients with multiple in in combined effectiveness be in resulted studies, may antibiotic effective have These there of study[385]. also that evidence another suggest suggestive was in crobes[23,25,386,387], Some was it found approach also infection. tinidazole) but antibiotic was pneumoniae and sclerosis infection, The C. roxithromycin of pneumoniae scle- (minocycline, circulation[384]. recent evidence Chlamydia multiple protocol show venous been needed, treat antibiotic extracranial have is to combined there in research a attempting improvement and more of promising much sclerosis, months Although shown multiple 6 have is infections. on diseases chronic patients autoimmune of pollution[381–383]. rosis the role air of the to well-known supporting linked most advances been has the autoantibodies, of by One destroyed are pancreas the of cells 31 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. rpsdta hsmyb eae oa neligcmo ahgnss46.TePME hypothesis response. PHMHEC stress The PHM-related pathogenesis[426]. common been common has a underlying it of an and part analysis cystitis, to is of interstitial related it variety and illness[425]. that a be IBS of using suggests syndrome, may years. the fibromyalgia studies 3 this years for by in than that but of supported out more ME/CFS, proposed is number for averaged for predominance ill only been the system not been nervous have by methods, had sympathetic would who stratified whole, those disease the not in early On early detected had in in they state they activation downregulation with pro-inflammatory or immune if variability the exhaustion the rate found immune that stratification, finding heart been the the lower analysis[424]. have is the Without of not stratification in association of included would the is importance ME/CFS fatigue the that of of indicated severity ME/CFS[423], example response. if in study sleep, Another stress clear found recent during and the been variability A consistent with has rate most studies. associated sleep heart is all system during ME/CFS low activation nervous in of system sympathetic not case nervous the but the sympathetic of is shorter-term greater activation or stratification for of milder Evidence of indicator the importance studies an Otherwise ME/CFS, the is illness. investigate which of of successfully example length patterns. to recent or the that A illness negate found even of been or severity has nema- dilute has on that some will It based aspect state, cases in years. stratify important hibernation-like found to 5 an conditions hypometabolic, need last is adverse often a state the in downregulated over called survival or recognized allowing been hypometabolic developmentbeen state has this the hibernation of that highlighted development (a system They todes[409]).The dauer immune and ME/CFS. to the similar of diet of perhaps aspects elimination downregulation many an subset a reviewed showed a comprehensively of in study al[411] symptoms improving A et gut in hypothesis. Morris along successful permeable was PHM PHMHEC wall more abundance the gut patients[422]. low and the of ME/CFS of repair inflamed of part invasion helping at an increased is aimed postulated across intervention that inflammation, nutrient the with translocation microbes with associated microbial other compatible species of with of be increase would incidence an This diversity, increased wall[421]. microbial disease[420]. of gut autoimmune signs in of ex- reduction history and of a family showed elimination and study of since autoantibodies the A ME/CFS of disease, development is in frequency skin implicated helpful the autoimmune increased been be has an an Autoimmunity and psoriasis, to is ME/CFS[419]. with develop there found allergies patients to been likely that preexisting more showed has ME/CFS. significantly study between were that in recent found approaches association A are the foods[416–418]. an hypothesis acerbating of PHMHEC shown one the And have to ME/CFS[414,415]. related studies factors discussed instance, previously and For anti-oxidants. the Oxidative to stressful of relative sleep[412,413]. all infections, increased energy Virtually by unrefreshing are cellular oxidants triggered and in when be abnormalities stress[411] occurs apparently brain[407,408], stress oxidative can the nitrosative and of that nitrosative inflammation cause involves unknown production[409,410], and of toxins[300] disease and/or that complex events etiology a underlying is an ME/CFS and syndrome infection fatigue polymicrobial encephalomyelitis/chronic Myalgic grade proportion hypothesis. a low PHMHEC least the at a of that have show framework to the may and mothers[406]. beginning fits bacteria ASD are their potentially ASD and of with in patients a studies patterns individuals However, ASD in needed. dysbiotic of of is behaviors blood detected research autistic-like more the study course, to in Of recent fumigatus, led a A. in diet Interestingly, fungus, present fat the study[405]. is saturated including one symptoms, fungi, high in gastrointestinal westernized without model A or mouse ASD[397]. with with individuals dysbiosis, many gut incidence[396,404]. involvement, ASD microbial with Regarding associated been has pollution air to 32 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. h netos hs upesn h muersos un u ob epu nmn ae,a es o a for least at cases, many in other helpful combating In be as to here. far out as discussed benefit turns any, diseases response if the immune little, with the of damage, suppressing many tissue Thus, in causing immunosuppressive infections. is why effective is the response explain that moderately system’s benefits could response immune least infections, that immune the opportunistic at words, an trait and with apparently low a PHM together are virulence, largely the necessarily virulence, have low targeting medications of would not if and in level is surprising common lower effective be very This be virulence would researchers. not not hypothesis, of of would current attention level the it the in high So, PHM escaped al[433]. the a of et typical that Casadevall microbes, by idea abundance discussed that the recently disease consider microbe, autoimmune to the of interesting cases is the to It disease, leading autoimmune debilitating. an perhaps and with extensive, fatiguing individuals contribute more some be in certainly are be also and would might might expected, factors invasion/colonization is involved genetic variation PHM would significant strains and self-tissue course, component microbial with Of Cross-reaction well. inflammatory the immunogenic. as stays additional more diseases system significant and/or virulent autoimmune immune a more contribute the these perhaps immune but where in number, the illnesses in perhaps fewer autoimmune and effort and well-known years the activated many few downregulating from vigorously first of differs approach the advantageous. downregulation be alternative in This might the the individual microbes or If effects, the the downregulated standpoint. combating debilitating killed immune evolutionary a in increasingly not the an toward expended have has from by shifting shift microbes itself perceived systems reasonable other threats response metabolic a and external ME/CFS considered and PHM and in be immune underlying invading internal might primary involved the the This the variants to is state. with PHM genetic lead hibernation-like virulence battle eventually and/or low constant relatively might infections many The system of triggering invasion ME/CFS. an more of that PHMHEC important. with or cause be as the might studies one least also factor, other at it be contributing several be causation, may a could discuss chemicals there be they the could and Although with substance toxins illness toxic associated particular microbes their or a that contaminants in thought suggests surveyed chemical factor hypothesis they Although initiating patients an results. ME/CFS adequately the been similar not of have may 20% opportunistic might buildings that secondary sick found exposure [300] more possible al or colonization/infection, et environment. one Chu PHM optimal in many an more of acquired even the in level changes and of when the metabolic even some buildings normalize least and all that at immune as where be In seen and one symptoms. might be to infections to might it syndrome contribute ME/CFS building cases, that of sick exposures severe cases and of microbial some sources allow concept Perhaps environments microbial the ME/CFS[430–432]. and outdoor of contaminants to extension chemical similar an from be involving result can to that proposed symptoms been has thus has and syndrome infection and fight building oxidative to Sick mechanisms observed system’s The immune control. the expected. to of and be attempting part PHM would is important with apparent an system colonization/infection are and immune ongoing compounds stress the of nitrosative result nitrosative that a infections and primarily secondary oxidative expos- be involving possible chemical to environmental cycle hypothesized with vicious is sometimes imbalances apparent PHM, immune to the related Thus, be microbiota, contributing. to altered here ures PHMHEC, from proposed are the differ conditions behind novel conditions principle The current hypotheses[429]. underlying hygiene when field the and the i.e., fact, from exposure in mismatch, concept chemical/pollution is, important evolutionary environmental cycle an and an is damaging medicine mismatch is evolutionary Evolutionary of evolved. there of type organisms when the this which is under to this conditions rare. leading to be genes thus exception any and An selection since natural ability indefinitely by the have persisting eliminated ME/CFS. animals cycles be other in and would vicious occur humans such to that probable hypothesized avoid seems is to it stress[411,427,428] perspective, evolutionary nitrosative an and from oxidative However, involving cycle vicious A 33 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. httegetrtelvlo eann H,temr rn h ain a et ies eurneand recurrence disease to be may patient the prone more the PHM, proposes remaining the the problems. hypothesis of cases, of health PHMHEC some level the In other case the But cases. the anti-microbials. all greater current in in the necessary with and that be treatable HIV, not be may addressing might is issue infections is PHM it secondary the it AIDS addressing AIDS, infection, of PHM. 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There of factors, particular be disease[352]. advantage genetic a thus take of with and development that together the develop agents trigger agents, infectious to infectious be system immune These may the there of diseases, suppressing/dysregulating induced these of many In providing thus tract, digestive infections and Disease-defining mouth the is enters environment it likely the diseases. addition, in also inflammatory In surfaces inhaled among to framework. linkages is spread PHMHEC easily potential that the are further anything into skin only And the fit colonizing are inhaled. may microbes urticaria) and also any they vulgaris, that however, recognize pemphigus to article, important dermatitis, this atopic in (psoriasis, briefly discussed inflammation other involving some diseases in to Skin muscle absent analogous itself areas. painful is or maintain particular Inflammation This a rare in Involving could body. or abundance very Diseases microbe the in rash are Skin A varying in a extent[254,442]. they despite presence spatial human of if a a through area even maintain in stability still the that, indefinitely maintain may like so systems they areas, microbes ecological blood), several of how the or reservoir (e.g., one a compartment in provide tissue from the PHM may result with abundance joint, also cross-react low could or that inflammation. of area food/inhalants local and particular presence environment affecting a The the thus in in areas, pain PHM painful and in to PHM the variation in exposure in variations The of PHM of areas. level result affected the a IBS[301]. in be the and variations could in migraines[440] This levels intensity[441]. like and rate microbe conditions pain, location significant other widespread accompanies in a vary by commonly often characterized at It pains is Fibromyalgia found disturbances[436]. syndrome is sleep Fibromyalgia diseases[436–439]. and condition, autoimmune fatigue autoimmune of an number apparently a in not although well. as syndrome, ME/CFS Fibromyalgia in expected individuals microbes, be to of might Syndrome range due differences wide Fibromyalgia individual be very a of the could including types hypothesis, patients possibilities These with PHMHEC ADHD inhalants. attention to, in the and react in additives they studied of items dyes foods, dyes light ADHD particular and which In food food to ME/CFS controls[435]. to as to in and healthy differing reactions common reactions infection than regarding more on chronic be often results to allergy, research more conflicting in found involving fatigue from hypothesis been ME/CFS experience results has PHMHEC ADHD of adults inconsistent the (ADHD). model resembles the disorder that hyperactivity a discussed deficit ME/CFS presented also regarding al[434] They hypothesis et stress. prior Bellanti a respects. noting some worth also is It time. of period 34 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. r lotogtt ecmo eg,nnlegcriii a iia yposadpeaec sallergic as prevalence and symptoms similar has rhinitis reactions nonallergic disea- non-IgE-mediated (e.g., that autoimmune considers common some one be if least so to reactions, at thought IgE-mediated for also in test are approach only studies important the of an ha- Many be some and may activation, diets cell elimination have mast ses[472,481]. reduces that studies which suggested Some omalizumab[478–480], ve thyroiditis[477]. IgE-targeting from Hashimoto’s sys- Crohn’s benefits and arthritis[468,469], colitis[474], shown rheumatoid ulcerative spondylitis[317,394] sclerosis[467], psoriasis[473], ankylosing multiple vulgaris[472], disease[308,475,476], be pemphigus autoim- diabetes[465,466], in often erythematosus[470,471], 1 found lupus to type being temic increasingly as proposed PHM is such control is cells diseases, mast to mechanism involving mune system typically protective allergy/hypersensitivity immune this food the of And of seems Evidence invasion. above. attempt it further years[463,464]. valid, discussed the against is as recent in allergy/hypersensitivity, hypothesis protect role in to the and important related appreciated if an body because, increasingly playing hypothesis the been often PHMHEC in are has the to they cells interest that mast particular likely of of are role PHM cells the to Mast due disease, environment release the autoimmune and in In degranulate widespread and to to body due the cells be in mast might antigens MCAS for cross-reacting whether colonization/infection. tendency and consider PHM increased to unrecognized interesting an to allergic-type is to reactions by It related characterized substances[462]. not is be other and and to has histamine recognized thought reactions being are these increasingly that is been behind reactions involved. (MCAS) have mechanism likely syndrome reactions activation the are Food cell cells Although the food[418]. Mast mast well[461]. to the cases, as reacting ingesting many were POTS after in have they hours with determined, reactions that for patients been food unaware delayed other other being often of in typically are were variety patients found reactions A reactions the the ME/CFS. milk with had since nonallergic ME/CFS, who food that in adolescents implicated and found activation cell adults been al[417] mast young also et that in proposed Rowe POTS been elevation POTS[460]. to has and related hyperadrenergic it (POTS) And this hypotension patients. some underlie orthostatic in postural may potentially adrenalin, disabling hormone, and severe, And, stress-related allergens, between the activation[459]. connection of in cell a avoidance mast also to is cause contribute There can to pro- stress proposed can of is activation level response cell high stress PHM. mast sufficiently the response, involving a earlier, stress reactions discussed neuroinflam- and the allergic of as response[125], in cells; involved production stress mast the is a with in which duce communication cells axis, bidirectional (HPA) glial diseases[455,456]. in and adrenal of is cells pituitary range mast hypothalamic studies broad between other The a interaction many mation[457,458]. in also well-documented role are a a There important on is infection[454]. an infections There colitis[451]. chronic play bacterial prevent a fight likely in help not cells effect can did mast negative an and that but a healing[452,453] create showing have wound dissemination cells can proper bacterial mast but for study that basis against helpful Another short-term be indicated protect virus[450]. to study dengue help appear recent with could cells infection A Mast against cells grow. protect mast to to cells continues that the T showed cells delta in mast gamma by with occurs synapse played are immune as neuropeptides[449]. roles they and histamine, of and Mast cytokines list like mediators roles[448]. as The numerous of molecules, be such secrete range be molecules, to preformed also wide signaling thought to a They of many are anaphylaxis. on known release by take as cells activated been immediate to known Mast evolved reaction long an eosinophils. and allergic have cause system and life-threatening immune basophils They to the as degranulate functions[443–447]. of such components cells immune cells, oldest of the other of array with one wide along allergy, a 19 in in involved the involvement in diseases their discovered related were for cells and mast autoimmune Although allergic, in involved are cells Mast th etr,te aeol eetybgnt eappreciated be to begun recently only have they century, 35 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. eotdbnfisfo ea rvgtra it[9,9] huaodatrtshsbe eotdt be to have reported diseases been rheumatic has diet[497]. with vegan patients arthritis or on Rheumatoid vegetarian diet a diets[495,496]. of by vegetarian effects followed patients asthma or fasting the long-term by vegan assessing of improved 92% Studies from in diet[494]. medication benefits for the need reported on the products and year symptoms a animal reduce to after and be found was will meat diet hypothesis vegan of A PHMHEC consumption the high to vs. relationship diets their explanation and Plant-based unifying diets a of offer types on might few literature contributing a food/beverages The simplify, factor in approaches. to important dietary PHM discussed. contradictory, so particularly of apparently been vast, a effects have sometimes is diverse, be factors The diet by dietary could diets. achieved has Many PHM different benefits diseases. This that of for inflammation-related microbiota. here effects in gut the proposed years. studied 50 the to is been last shaping it have the however, in diets over implicated; conducted of diet approaches range of dietary wide of importance A studies the many of the for understanding implications increasing Hypothesis important an PHMHEC is the There and Microbiota Intestinal the the is and allergy/hypersensitivity Diet, methodologies inhalant new and by food revealed that reactions appears thought. of previously it types than involvement, extensive varied cell more the mast likely of of discussion evidence related previous tests increased previously, the allergic discussed from in As involved promise. So, showing cells asthma[493]. are blood in eosinophils white common of and are to types basophils eosinophils limited other to are of are reactions levels hypersensitivity basophils well. and Increased and allergic as reactions. Eosinophils important conditions cells. the comorbid mast that involving imply the compatible to those in is meant involved overgrowth not being is intestinal IBS discussion PHM small This in cross-reacting microbial success and limit aforementioned foods that The to diets here[492]. hypersensitivity relevant and with also antimicrobials is diets, disease) conditions elimination reflux autoimmune of gastroesophageal and gastroparesis, allergic (IBS, disorders several gastrointestinal to functional inflammatory arthritis linked to that rheumatoid cells study been in mast A have linked severity cells also mast disease has and research of histamine Allergy, Other markers disease. patients[486–488]. diseases[489–491]. the be sclerosis studies of multiple to pathogenesis linked multiple of in the cells also implicated discussed extent in studies mast role al[485] The Other their showing et cells. tissue[484]. supporting groups patients, Rivellese beta pancreatic pancreatic by research human pancreatic the different review in to insulin-producing by A damage the degranulation allergy/hypersensitivity[322,465,466]. with near cell and correlated found mast also been T1D was of have infiltration cells evidence For cell mast issues. with mast of the along of levels some high cells, clarifying of diabetes, islet promise I show samples type human in of studies the instance, cases, in some mutations least particular raised at the in issues Fortunately, to by the related illustrated of diseases as some other used[483]. limitations least and models their at autoimmune have animal diseases, in clearly involvement inflammatory models cell and Animal mast as autoimmune regarding models. many self-antigens, animal to and used linked has inhalant been research have food, cells microbial, mast between Although reactions allergy/hypersensitivity cross-reactions hypothesis. for PHMHEC as role the larger well by being a as increasingly proposed uncovering are for diseases allergens inflammatory potential autoimmune bacterial great autoimmune, previously, in a mentioned in is As food/inhalants there larger. much Thus, to discovered. likely allergies/hypersensitivities is diseases of related role and the then rhinitis[482]), 36 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. onre.Teesuisso ik ewe h dpino h etrie itadternwyacquired newly their and diet westernized the of adoption the developing in between studies links from come well. show have as diseases studies inflammatory PHM would and These unique own and diet countries. between contain its foods connections have might clearest processed may the which many of sugar salt, Some to And added of PHM. recently. also amounts until of levels is high growth conducive significant Sugar fuel and environment at PHM[140,513]. likely to an additives include exposed to contain that been lead may communities not could have microbial foods humans This processed that niches. and strains overt addition, available survive, and to the likely In species would related fill in microbes increase to microbes an other occur of to to microbes, might presence microbes of radiation diversity the animal/plant-associated adaptive and reduce any an adaptability much would for the consumed preservatives time with often However, and allowing are spoilage. They refrigeration fruits, reasons. course, be and multiple seen. for Of also vegetables PHM benefits increase. might than in the higher harvest it for be after Thus, reason to longer the expected products. likely be of would animal would part it has and foods itself, be Processed consumption of foods might and products. this vegetable processed in animal and and of beneficial PHM and probably consumption fruit in sugar is reduced lower increased and foods foods, by plant that conditions ultra-processed of accompanied than noted medical diversity less less be and they 2 involving consumed intake diet had And who greater Mediterranean-style those the who day[512]. to Although follow- a adults per 6-year compared to day older a servings linked per with in 3 vegetables been study mortality and/or to A according fruits all-cause years[511]. equal 5-6% of 26 in by servings or to decrease mortality more 4.6 or all-cause each 27% of 5 reduced addition, periods a humanconsumed day, follow-up In found greater per with attribute[41,45,421]. to servings period studies linked positive 5 14 up of to a been Greater meta-analysis up vegan[510]. has be a vegetables, or week) to to omnivore and/or per considered as fruit types such been of pattern, 30 serving generally dietary than particular has (more a diversity diet than microbiota so the more in diversity, microbiota plants gut of diversity greater A products[506–509]. foods animal processed of and components and harmful diversity PHM Thus, possibly Plant meats[505]. of processed list processed less the inflammation than highly to cause effects why added can health be explain negative that might partly with PAMPs components might linked microbial microbial This strongly of PAMPs)[504]. more some levels or are by elevated meats patterns found reported molecular has diets associated including meat low-fat fat (pathogen sources, processed Fats of saturated of of low success methods. variety study particularly the sclerosis[502,503] usual A a with in multiple fat), the from in factor from with promise petroleum a calories shown undetectable from (20-25% be has that levels PHM diet intake, might PHM Swank more at PHM the low-fat have even in to The to researchers[500,501]. reduction due perhaps prone is Thus, levels, animals be pollution. low from air also at fats might saturated fat interesting plants petroleum- consuming An in in them. from with case for present problem the habitat the favorable be be might a of might as be part fat, might that in provide rich animals is to environment that possibility fed an tissue to fatty potatoes well-adapted the and are microbes, corn PHM adapted agriculture, soy, the (e.g., of industrialized proportion them in a for be conditions If natural likely crowded typically would the not PHM are the in that that for extent likely diets opportunity cattle). greater seem consume more would a animals be It to the would animals/humans. where animals there in colonize/infect because living to is for able This adaptations wider humans. acquire a colonize/infect harbor to shown could potentially has PHM would that which animals PHM diet, raised conventionally Mediterranean of that the range predict of would features hypothesis the PHMHEC described[498]. of The been one around has is diseases[499]. populations diets products many animal-consumption certain animal in of reduced in level benefits or diseases reduced vegetarian inflammation-related a vegan, fact, of near In incidence follow reduced that world and the span life longer The 37 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. egt o hssuysget htteei oehn bu lr-rcse odta ed ocause to tends that food investigate. ultra-processed to lost factor about same actually contributing the something diet a with be food is might diet processed there PHM minimally food The that the unprocessed gain. suggests on weight relatively and Those study consumed a overconsumption macronutrients. food this given and ultra-processed those So, of fiber diet than weight. fat, a weight sugar, given more adults of inpatient gained amounts that and showed al[534] calories et more responses Hall sugar by blood study shaping recent be A weight. may diet gain the to PHM in propensity potential antigens colonization/infection the cross-reacting the PHM and and supports to PHM related previously to response discussed exposure stress continual the results and hypothesis, test PHMHEC sugar[322] hypersensitivity the blood to food and According index[320] on connection. mass example, based For body diets pollution[381,533]. in considered. improvements by air significant be shown the to should needed, incidence are this studies T2D and more and Although well elevation[532] as sugar by exposures blood inhalant influenced linked reflect partly have may be studies sugar food might the blood and foods Thus, the in certain food stress. activity[531]. and Increases of to intense the response consumption anticipated response in the stress adaptive for PHM after the sugar body’s to increase of human blood sugar response part the adequate blood stress as requires the a increases which of reflect typically flight, magnitude might or sugar fight food Blood for a PHM. the need to with PHM. to response cross-react According food-associated in that microbiota. the antigens intestinal by increase influenced the sugar in be blood they changes could A and changes with individualized, microbiota patterns highly observed were sugar increases the blood sugar hypothesis, monitoring[530]. the blood PHMHEC sugar correlate highest indivi- blood the to This to. constant caused overeating. able react doing that subsequent were to group foods and research happens the cravings a that person by food found a observations They sugar, with that diffe- concur blood PHM individual to affect the from appears from could stem duality arising reactions partly hypersensitivities could food microbial loss involved. resulting weight and The factors in food other success the are weight subset that in there genetic lose predict rences Apparently, a would several would relationships. participants in hypothesis on predictive study PHMHEC successful no data which The found determine analyzed was and to They diet diet try overall[529]. particular to each superior levels a found secretion on being insulin diets one baseline diets[528]. low-carbohydrate neither and low-carbohydrate markers with to and diets participants, low-fat low-fat study using comparing of success study equal been recent has A there rhinitis[524], studies, allergic loss weight asthma[523], cardio- Among to and diseases[526,527] (T2D) linked autoimmune inflammation diabetes been several of insulin to have and risk pressure, obesity linked increased rhinosinusitis[525] blood and/or an been chronic high with syndrome has as associated Metabolic itself such is disease. and conditions Obesity vascular fat includes diet[522]. abdominal syndrome westernized increased autoimmu- Metabolic and a and syndrome. resistance allergic to metabolic including linked as conditions, well been inflammatory as of has range and wide diseases, a ne with be associated been to has loss need Obesity weight might for that nutrients diets out and and points Obesity IBD also in that used exclusive review diets than recent Several effective diet[520]. a 75.6%[521]. each more of in in significantly rate summarized This supplemented animal be remission alcohol[520]. are soy, steroid-free to and dairy, conditions sustained appeared chocolate other gluten, a nutrition coffee, with eliminates enteral products, Crohn’s nutrition, essentially partial packaged a enteral that And and with al[519]. developed canned combined et emulsifiers, Chiba CDED been by meats, has proposed processed been (CDED) fats, has diet approach plant-based components exclusion A many disease of diet. avoidance westernized involve with typical interventions promising a rates some of asthma research, greater disease sweets[518]. bowel linked and inflammatory India In sodas in like study foods, A processed diseases[9,514–517]. of autoimmune consumption and allergic in increase 38 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. H eas faodneo lr-rcse od,gue,diyadsm omnalres Paleolithic allergens. common reducing some as and far dairy as gluten, benefits some foods, has ultra-processed likely of diet avoidance Paleolithic of the because perspective, PHM hypothesis trial controlled PHMHEC randomized the been a From patients[537]. also in sclerosis has measures multiple diet quality-of-life Paleolithic remitting and quality- modified relapsing fatigue health-related A in in improved thyroiditis[544]. reductions significantly Hashimoto’s significant to disease[538]. in with led significant scores bowel associated also found burden inflammatory diet diet symptom Paleolithic with legumes, this and a patients dairy, evaluating of-life included in study gluten, that A inflammation approach include inflam- lifestyle vegetables. avoided endoscopic promote A nightshade and foods to and symptoms proposed The oil of been diet. seed improvement have Paleolithic industrial that and autoimmune foods grains an sugars, certain dairy, refined called of eliminate been avoidance involves typically has fish[538]. also mation diets and that meat These type diet nuts, Paleolithic the eaten. vegetables, A mimic have fruits, to differences would of attempt consumption detect ancestors diets encourage to Paleolithic These and fail years. our legumes may recent that products, in reactions. animal diet investigated patient studies. increasingly or of of previous meat individuality been in have the red done diets of as as Paleolithic such because foods, scale of food, amounts population of small large type of a one tests on on modest brief hypersensitivity these focus with food that evident that modest noted multiple be Studies They that by not self-antigens. driven suggested likely with be would They cross-reactivity might controls. reactions and disease healthy complexes this to immune in involving patients joints reactions arthritis on attack levels rheumatoid antibody system 14 specific immune comparing food the non-gluten when increased significantly these IgA) found of IgG, and samples absorption (IgM, fluid intestinal greater gluten tested a al[481] from et the to twoHvatum permeability Thus, avoiding related above stream. intestinal from be blood the increased the sometimes PHM. benefits with The into including might allergens/antigens report permeability. those components, consumption and on people in microbes gluten effect of some just with to translocation its problem ability reason not in to increase its everyone, the an due is in whether allow partly would considered true to be be is as may should which where arises gluten that recognized wall, disease, question consumption now intestinal Celiac The gluten is permeable decades. conditions[543]. to sensitivity more recent regard gluten a with in Non-celiac cause factor contexts previously. Another different mentioned well[543]. was many as mandatory, in previously. is discussed discussed avoidance as being gluten involved, are and be rhinitis may diets might allergic mechanisms reactions Gluten-free in hypersensitivity IgE-mediated common other conditions with is since allergy-related associated sensitization enough, other Food foods be the helpful. avoiding not make be only can to However, rhinosinusitis[541,542]. foods tend chronic allergenic allergies of food avoidance dermatitis[540], and worse atopic and asthma[539] In diets elimination patient’s Food disease. a proportion chronic from significant a a support combat by and maintained to and patterns successfully attempting training be eating when some can change patients patterns with completely of eating that that new nutritionist, plans appears and/or dietary It physician certain foods[537,538]. processed from dense ultra-processed results calorie eliminate mood. In encouraging fact, or some In microbes. energy obesity. are addiction[536]. in the associated higher There lift food and containing contain temporary to addiction a food the that linked food cause consuming that closely might in foods to are that factor foods for response feeling contributing foods for stimulated in a craving a craving occur be a cause a might could could may to This effect had this microbes stress and humans extended gut PHM mild if be some of a levels that might “benefit” people, speculated would some This been for microbes fuel[535]. has addition, the It for since cravings. use cravings, of microbes role on the effect is an obesity have to related issue Another 39 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. on ntesi,i h i n nfo,mgtcosratwt te irba legn rmpeanuts. from allergens vegetables to microbial to comes other it reactions when severe with exist may the cross-react problem be underlie analogous might might An potentially prevalence. food, that could in soy, increasing in allergens, been from non-microbial and have that originally peanut’s peanuts, air peanuts to allergens the the allergies with microbial in of combined Plastic-related of skin, And years. level include the 50 increased that on an last plastics of found of the development types in the certain legume, to in related another microbes be legume-related plastics strains. might of diverse plastic and presence components the soy-derived the with species all that novel associated to types, hypothesize many due microbes many might to occur One effect of the lead might what that could plastics affect radiation world beverages, to might adaptive modern and The exposure that our food ingested. pervasive the in factor and our current into inhaled another with when the integrated contact is have with so may close plastics[553] consider, in become in to those can term ingredients interesting including microbial plastic the soy-based different is have on and of plastics It survive Different plastic, use communities. them[551]. that on of the all microbes thrive and remove the cannot and communities plastic measures survive of extreme The even that some that environments. microbes that plastic marine the found in have of communities[551,552]. conducted Studies study these been to describe has to led used that has is research ocean plastisphere some the consider of microbes. detected to pollution the generalizability reflect of interesting of abundances did lack patterns the is the affect microbiota microbiota for It PHM fecal explanation abundance These low possible person’s days. undetected A individual’s a study. several an the of previous that in be composition the individuals might other the from more to nutrients, that generalizable general, conventional not found were not in al[550] but et And, choices, microbes. Johnson research. that abundance dietary by more low PHM shows study including needs abundance Research recent needed, packaging. low also A is of The themselves food/beverages effects in considered[548,549]. materials microbes the packaging be on likely at the to research present. would look from issue PHM which should originate important of harvest, transport research types may an since of the future time effects is affect that of the contamination themselves mentioned length at packaging might cheese the provenance looking also as and to including authors such transport related done, The Plus, foods often be abundance. fermented are to significant PHM uncooked issues needs affect size. detect two included research sample not These low that more to provenance. could meals that due and and noted from probably patterns, study were They eating yogurt. pilot microbes different and of three small investigate from numbers a to foods largest from the begin The in data to microbes presented the food al[547] in in differences et microbes Zivkovic at reach example, can looking For microbiota. that begun gut pathogens have the foodborne groups affect and research they microbes in how Some spore-forming detected just be intestines. transiently not large could is foodborne and the it intestines that and shows found stomach was This the it samples[546]. through microbes, fecal passage of survive levels to reduce able acids were bile microbes and acid stomach enzymes, trials salivary Although small the diet, of food/beverages Mediterranean needed. several in are vegan, that trials Microbes (e.g., concluded clinical and here larger that arthritis discussed concluded inflammatory diets they However, of the benefit. context are of significant the to demonstrated that several in responses microbes study. reviewed diets) in the a recently elimination differences of of al[545] part individual more as et explain contain to nutrient Jethwa might partly assigned whatever adequate might disease be that might and their This consider patients to developed progression. allergies/hypersensitivities that interesting they disease diets food be when their might to also eating to attends It was contributing conditions. also person some a that in helpful diet diet especially vegan be might near animals, intake or raised naturally PHM. vegan more reduce from A help products to animal expected of be consumption would the emphasize which sometimes least at diets 40 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. a enfudt rcd h eeomn ftp ibtsmliu,adsaeascae ihchronically with associated disease stress a chronic mellitus, of diabetes this 2 indicative and type variability levels[571]. sugar of rate sugar development blood heart the blood in lower precede high increases Interestingly, to to effect. found contributes been aging-related chronic that has in the to stressor PHM to response to a resistan- add allergy/hypersensitivity in constitute insulin would that activated may and suggests inhalants sugar be hypothesis blood or also PHMHEC high food/beverages to the to previously, lead appears discussed can pathway research pathway relationship As more GH-IGF-1 PKA-RAS ce[567]. a Although the the hypothesis. demonstrate of that PHMHEC activation to the Increasing interesting appears and stress[570]. is above PHM it to mentioned related pathways needed, be aging-related is might 3 that the stress physiologic of abovewith 2 the onset. on to disease relevant research early be New diabetes, may of as hypothesis cases such PHMHEC aging, and The of interest. aging diseases great of get of IGF-1 sometimes theory is adults and diseases, young autoimmune relatively receptor aging-related and and hormone on children cancer why growth effect to severe as beneficial question to a The pound leading only have per mutation that to however, g a appeared activation; .36 pathway with GH-IGF-1 to GH-IGF-1 deficiency[569]. population Lower .31 the a 65[568]. reduce (i.e., in age to intake signaling/diseases under beneficial protein those be many lower yeast, to to instance, with thought diseases, For applies done is autoimmune humans. weight) was including in work body age, original corroborated of with the being increase of been are much that have Although diet aspects diseases of fasting-mimicking disease[565–567]. combat result cardiovascular periodic to a growth and a ability As and/or hormone-insulin-like cancer their (PKA-RAS). diet growth evaluate sugar A-RAS are protein/low to kinase low pathways studied protein a The pathways, and these alteration. (TOR) aging on rapamycin promote dietary research of can aging? to target that of responsive pathways (GH-IGF-1), biochemical diseases be hormone-1 several to get examined appear has increasingly process[563–565] that people aging young the on do Research why stress: and hista- diet to H1 hypotheses Aging, tricyclic the histamine-related block the dose above. to links discussed low ability cells syndrome very their mast activation to by cell of due release mast effectiveness be histamine and to course, The and allergies/hypersensitivities appears of pathogens hypothesis[561]. insomnia And to pro- PHMHEC and receptor[562]. reactions was ME/CFS mine the hypersensitivity ME/CFS in and to sleep explain histamine for to similarities of antidepressants hypothesis some role A the has noting. included that thus worth that foods are Dechene[561] fermented by histamine of potentially posed with be set histamine to connections limited high thought additional more are some Some foods a fermented tolerate Specifying the since might contain. useful, in individuals be they histamine would the PHM PHM, individual beneficial[560]. of the an other same for effect to and the reactions the due adverse histamine to to cause others releasing add reacts not and would likely and degranulating This everyone foods PHM. cells not by mast certain produced Since ingesting and/or PHM allergens after food. basophils more patients to have to in response to increases due in Histamine tend partly to substances reactions. also interesting be of might is pattern content, could the microbial It foods explain higher intolerance[556]. partly their histamine might with of this foods, and diagnosis histamine down the high regarding breaks that in controversy consider that still useful enzyme is be there the benefit[559]. to However, some Low of reported shown yeast. Supplementation been has some have oxidase) urticaria[554–558]. and (diamine foods/beverages bacteria chronic histamine of fermented including types of many conditions, reduction by alcoholic some include produced yogurt, which is sauerkraut, Histamine cause diets, are can chocolate. histamine Examples that and levels people[554,555]. tea histamine intolerant coffee, higher histamine but and beverages, content some ideas, microbial for speculative higher reactions highly a adverse with are foods/beverages These certain adhesives[553]. are and There items plastic some investigating. in worth used seem being are which oils, 41 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. ievreyo ye fsuismgtb sdt ettePME yohss eerhi h areas the in Research hypothesis. PHMHEC for the implications addressed. test And be discussed. to will be used approaches will be treatment epidemiology might on and research studies effects stress-related of immunology, microbiology, types of of variety wide Research A Future for Implications any diseases. 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Data may be preliminary. ciiismgthv ob ogti eprlyr ouefrteecmaios50.Peual,PHM Presumably, comparisons[590]. these industrial for could from use microbes water to soil and layers the air deeper to in in exposure changes lacking sought the Soils and be the microbiota. interest, by to human for of have the called be might as in might activities changes microbes,” soils to to guide modern correlated “field to be a soils develop to ancient effort mined These Comparing an hypothesis. or of Eisen[589]. the PHMHEC part extracted Jonathan and the as humans microbiologist, evaluating other seen in Davis in with found be UC helpful might microbes along be studies the would petroleum, Studying of sources useful. types and their be plants would determining crust, and soil, earth’s environment water, the beneath air, from inferred from substances patterns of PHM disease And, and of Europe? 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Often environment the problem). cause built to beverages[579] that the microbiotas known and of preventing shifting are the foods Studies on that just regarding fermented focuses few so true in a research involved particularly or species, most microbes microbes probably Because abundant abundant the products. is most on agricultural That the or and results. on spoilage[578], chemicals, interesting focus products, yield man-made are to to of species tend start microbial studies may New improve. most focus great. adopted will previously, is widely hypothesis progress discussed become the for As test methods[574–577] potential improved to the as ability so but detected, the abundance, being developed, in continually some are low since methods initially, very challenging new be somewhat and prove may may microbes hypothesis the this of of aspects microbiological the Studying Microbiology 43 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. osmn ltndrn h etmgtla oafiuet eetsm ecin eas h intestinal the because reactions Not some considered. detect be to to failure less. need be a would also permeability to absorbed might intestinal lead be meal increases might to every antigens gluten test their nearly allowing that the in at permeability fact patient be during foods ability might the The gluten gluten-containing the it of pattern. eat consuming affect case, mites. reactions eating also people the dust the might usual many and is reflect foods their and pollen that cross-reacting accurately as like with any If to are ones, and environment food. tests reactions usual food usual the challenge the the tested to placebo-controlled just the syndrome, are double-blind of not allergy they in consumption of and oral recent as patient inhalants in of the the food level as of by a The just consideration experienced with include whether, the cross-react usually to consider that those in important to inhalants than do exposures interesting the different often inhalant is to are studies the much It done that because life. is reason be daily testing One could their where interest. reactions[595,596] hospital of food or area reported laboratory another patients’ are that corroborate inhalants allergens/antigens not and plant food for between occurred Cross-reactions also same diseases. the this autoimmune to if and have antigens to allergic hypothesis plant seem to PHMHEC would with contribute This the cross-react antigens[265]. for antigens tissue human implications microbial with significant plant cross-react reactions. if microbes food allergic human-associated determine cause refrigerated that to to weeksextent interesting picked to keep prone food be would less compared than would system be microbes It harvested immune might fewer foster plant’s have food just likely living to harvested would the food recently hours, food cases, The harvested of few most recently before. in so reactions a assessed. lower, that level for cause be expect microbial could would warmer the to reactions One kept ability in before. is differences weeks the harvested the that evaluate and reaction. food colder, could given kept between a One is to made that contributing be food microbe allergic and food-related could the growth, a in comparison microbial be involved might a be there instance, certain might whether For involved, test microbes could that are one appears microbes instance, For it what whether knowing test that without to microbes out Even for reactions. carried specifically allergens. be looking be known hypersensitivities, could could with packaging or procedures allergies food cross-reacting Fresh food of be comparison. for effect of tested the may sake be and could the compared subjects for be Human could cases time microbial some could of the in responses periods used at immunological varying and be looking for at microbiota tested. could studies stored animal’s soil looking but food the ancient studies on done[593,594], vs even effect Some food been Perhaps the have and foods. conducted. mice air grown be traditional and on conventionally also It from food dust derived and environment. soil, of food the soil built and types of urban content the soil different one use with in of but could with, effects housed effects one coevolved example, their the and they For that chow compare PHM. environment to lab and and exposure food processed farms of diseases same fed degree model the the that them are vary studies give could they in to used impossible since mice virtually PHM, course, be by would Of contexts. affected many in also utility are have mice important of be disease. studies diseases also Laboratory to would contribute related that research might and research of they of autoimmune how lines lines allergic, and other other Immunology: PHM are These of there hypothesis. role goals, PHMHEC complete research the the above most understanding evaluate the for the to accomplish in used to hypothesis be time some could this and take of would organs testing it various allow While in eventually likely resolution will greater supply animals likely with food manner. and are and communities humans there soil microbial of but the tissues analyzing world, reach the in would around improvements activities all Further industrial activity[591,592]. soils from industrial level from microbes surface far which places in to in are degree the pollution water in differences and air with associated 44 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. ietl hne htdces H xoue eraesrs n s niirba hrpe ol have would therapies and antimicrobial diet use incorporate and that stress approaches decrease treatment exposure, that PHM predict decrease would that hypothesis changes PHMHEC lifestyle the diet. general, on In approaches section of the combinations in Some above exposures. diet, environmental discussed probiotics, altering including were immunotherapy, hypothesis, and specific techniques PHMHEC the reduction allergen to stress medications, relation lifestyle, in modulating examining immune worth antifungals, are approaches antibiotics, treatment of range wide A investigations. likely immunological would and approaches microbiological they Treatment have to included, studies led were dietary they exposures if Many about especially included. microbe- questionnaires useful, be and if more could exposure even and the chemical be immigrants[517,600], with the associated on with the PHM done assuming cross-react the been than of might analyses Rather that associated exposures, incidence[143]. substances changes chemical of disease derived to cultural effects autoimmune due the on certain solely investigating dust linked are Examples studies silica effects that and further. and sclerosis[597,598] examining ones exposure[599] multiple worth include metal of examined be heavy incidence undertaken be might increased been could exposures to already intakes urbanization of have with food/beverage types that and what pinpoint used the studies i.e., help products of mentioned, to practices, been countries cultural various already in has in changes study the practices of addition, cultural type hypothesis[353]. In to that chain of relation cold example in the An diseases test out. various to carried of attempt be incidence could in occupations increase or the investigating stress. studies of Historical effects the of investigation the regarding and in studies axis aid Epidemiology in HPA could gained sections knowledge the above the with the addition, interactions and In in their sections. allergic[111] discussed and previous approaches and in using responses stress discussed PHM hypersensitivity as between the response, relationship about stress account into the learned the take that been on undertaken has be done could what approaches being research targeted research However, diseases[109]. significant autoimmune already is There research medicine. current personalized the Stress-related with more infections accord for and in aller- opportunistic need are autoimmune secondary the considerations and These of multiple allergic, PHM. microbes recognition to of in variety the what response wide toward found a the in trend pat- to patterns to response patients important the activation due obscure among with be intermingled system may differences could immune diseases individual diseases within complex inflammation-related of heterogeneity the the aware Importantly, otherwise be terns. since to involved, are arthritis important instructive. types gens/antigens especially rheumatoid be multiple be some approaches, will would treatment for analyses It various immunological markers including in-depth inflammatory extensive, the and more and driving tests even are allergy/hypersensitivity symptoms revealed is of allergy factors on that food what for effects work determine testing Further significant prick help patients. skin had would that showed This that al[469] interventions. these et microbes. Karatay foods in the various responses by other sources study immune of after A or PHM of role responses. measurements and the changes inflammatory the incorporate and diet during understand mechanisms could by better immunological therapies before, antimicrobial to affected the measured of of are trials be significance Similarly, diseases the could conditions. different elucidate unravel Biomarkers help of hypothesis to would reduction. PHMHEC features difficult This the be immunologic PHM evaluating for will how at useful responses of particularly attempts immune be studies the would that of be studies complexity would of great types the The interpret. made, and being progress the Despite 45 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. h ag ubro irbsta ieg ral rmkonseis hc a eetyfudvacell via expected[601]. found previously recently than was role greater which a species, play known species unknown from that greatly suggests is diverge blood, PHM of that the analysis numerous microbes magnify DNA perhaps would free of or food several number in of large effect and The additive skin several the the by course, issue. on explained of important air, be And an the sometimes can microbes. potentially in or abundance diseases antigens Hypersensitivity low difficult chronic and response. of immune cause microbes are hypothesized effect the other The to that alter problem. with so microbes PHM that the cross-reactions been rare effects of numerous and toxic have part very cases, and/or large diseases even hypersensitivity some a or involving these be in mechanisms to abundance of or suggested low causes are few, of the methods a ability current study, with of of detect role decades to The impossible despite why, elucidate. explain to autoimmune also difficult explain can to hypothesis attempting This hypotheses with main relationship the diet, of disease. the In most of combined allergic organs/tissues. for unites target and effects exposures essentially varied explanation the hypothesis and antigen plausible comorbidities, exacerbations increase this back cross-reacting a addition, frequent periodic the going the the provides and and diseases exposures, disorders, infections PHM chemical/pollution westernization these environmental these secondary in with of in to Variability some diseases common susceptibility least decades. these heterogeneity involvement. at increased recent of stress provide of subsequent connection in and and presence with the diseases characteristics hypersensitivity the accounts, disease these microbial, explain historical many to of in earliest as ability features for the the main account has to three can also the that hypothesis for hypotheses This explanation other disease any, unifying cause if might a gingivalis, they P few, that hypothesis. pneumophila, rare show are L. to PHMHEC quite There beginning as the is such be fits research aller- detectable, that cases, may easily some manner causing PHM more in a are And typically these in en- fumigatus. that A. of humans, post-hunter-gatherer some and are many a albicans colonizing/infecting there C. in Although detect, through abundant to stress. difficult disease more physiological and are to and that responses contribute microbes gy/hypersensitivity or that cause hypothesis the vironment explores article This might microbes Perspectives of sources and those Conclusions eliminating and cleaning, taxa, to accessible microbial not of if typically range crevices, are broad associated that small a areas Even microbes symptoms. instance, crevices. of reduce of for and growth the sources sought, cracks foster be on eliminating small could could with research i.e., microbes along detailed cleaning, of sources when do related other overlooked systems, previously to addition, mentioned associated conditioning In ones are useful air the that dampness. be like buildings with of made, in may maintenance office present be chemicals It could better an improvements the to difficult. in situations, just some abundant than more In rather are symptoms. become situations that with these can in microbes issues microbes to of the hypersensitivity sources involve home, might instance, or is that for avoidance building known, diseases much are some agents how the for about where However, learned cases pneumonitis. some be hypersensitivity aller- are of to involving there Clearly, cases yet conditions avoided. many has of be in much to treatment PHM, needs the what to of and comes needed component it important when an them. but of course, gy/hypersensitivity, to elimination of reactions to are, the lead would measures of approaches it Avoidance treatment elimination instance, For developed the treatments. newly just evaluating or to or widely. applied current PHM vary be whether might the could determine disease studies each to of necessary, in important types specifically be other be the required not in might is learned therapies What is antimicrobial cases. What severe cases, more some in In effective. important broadly be might most but the be to potential the 46 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. Data may be preliminary. rtflyakoldePtrKae,MD,adInRbrsTosn .. o epu omnson comments helpful for M.D., Roberts-Thomson, Ian and M.D., Kramer, Peter acknowledge gratefully I funding. Acknowledgements external without done was research determined. This be to diseases still chronic is inflammation-related role of microbial Funding rates PHMHEC a increasing of the of the by much sources in described How role phenomenon in here. some the least that discussed changes at argued played rapid be likely virulence could has use” the it hypothesis “dual microbes, the microbes, to environmental and some ability cross-reactions here, of of of PHM’s hypothesized factors nature abundance widespread the manner the and reduce westernization, the accompanying adaptability to in exposures ubiquity, helping factors also important the probably are Given are PHM showing the recommendations already above If disease. are the diseases. to that contribute that of cause cessation) (e.g., likely range that smoking lifestyle seems wide substances healthy sleep, other it a a adequate and of in foods aspects methods, benefit avoiding other incre- reduction a weight, and for stress healthy vegetables recommendations and current a reactions, with fruits of adverse accord as maintenance such in intake, the is nutrient foods, reduce hypothesis plant adequate hoped, PHMHEC whole is the of it that intake notable and, asing is temporarily could U.S. it validated, least the then, at be waysUntil in useful, hypothesis additional prove this fats to needed. in may should trans lead restriction especially that PHM, of may diets artificial products, the level hypotheses restrictive many of of in optimizing other knowledge banning dyes in and Increased help the food hypothesis foods. ingredients. natural instance PHMHEC processed artificial driven with improving the for fewer trend, dyes of on with recent food foods, research based those a Further processed petrochemical and been Europe. in of and foods has replacing changes PHM “natural” There the to and more the diet. led toward westernized of has consumers, the knowledge and This in adequate research sub- foods through both to processed effects by possible regarding negative them. be differ any to should that Opinions of responses it is industrialization our all, world, hypothesis, with global westernized not PHMHEC associated increasing industrialized, dietary mechanisms the if the neurological/immunological/hormonal urban, improve from most, in increasingly and arising change reduce an pollution here, significant stantially in air proposed a live reduce viewpoint be we The will to although there process. made westernization that being unlikely and are seems helpful attempts treatment- be it important could for choices, PHM and especially the treatments, laudable of in new understanding Although PHM developing better the a and cases. case, to effectiveness severe any and adapting and as In resistant safety such or term. treatment near responses, controlling the optimizing inflammatory for in chronic in approaches least modulate but at effective that preferable, situations, approaches be some be that might may be colonization/infection medications, PHM could immunosuppressive most It eliminating attainable. valid, always hypersensitivity is not the hypothesis or that anticipate PHMHEC be itself, necessarily the not may of If can It dangerous. and system PHM. immune prove in the the will as harmful to unknown, microbe is the reactions new handle PHM immune PHM, which to by the of precaution to colonization/infection a majority as related potential the evolved is reactions any perhaps harm For extent hypotheses. main PHM. what additional of the to of role whether know generation possible helpful not prove the the will do regarding and it we questions research to important future related many for research are stimulus the There and a direction current hypothesis and the this framework to presenting organizing respects, that many an in hoped as close, is is It that taking. research is for research focus a suggests hypothesis. hypothesis PHMHEC PHMHEC The the with consistent is finding This 47 Posted on Authorea 30 Jan 2020 | CC BY 4.0 | https://doi.org/10.22541/au.158035512.24828861 | This a preprint and has not been peer reviewed. 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