View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Online Research @ Cardiff

Gut microbiota, and the host: the influence of the gut microbiota on cancer treatment

Anna Louise Pouncey, Alasdair James Scott, James Leslie Alexander, Julian Marchesi and James Kinross

Centre for Digestive and Gut Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK

Correspondence to: James Kinross. Email: [email protected]

Abstract

The gut microbiota exists in a dynamic balance between symbiosis and pathogenesis and can influence almost any aspect of host physi- ology. Growing evidence suggests that the gut microbiota not only plays a key role in carcinogenesis but also influences the and of anticancer therapy. The microbiota modulates the host response to chemotherapy via numerous mechanisms, including immu- nomodulation, xenometabolism and alteration of community structure. Furthermore, exploitation of the microbiota offers opportunities for the personalisation of chemotherapeutic regimens and the development of novel therapies. In this article, we explore the host-chemother- apeutic microbiota axis, from basic science to clinical research, and describe how it may change the face of cancer treatment.

Keywords: gut, microbiome, cancer, oncology, chemotherapy, pharmacobiomics Review

Published: 05/09/2018 Received: 28/02/2018

ecancer 2018, 12:868 https://doi.org/10.3332/ecancer.2018.868

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 response a therapeutic re-establish could mice from untreated response. Fewer transfer ofpathogenic pre-treated mice andadoptive of vancomycin in thespleens Th17 cellswereobserved Th17 cells enteric lymphnodesandthespleen,stimulated T-helper 17(Th17)celldifferentiation resultinginanantitumouradaptiveimmunological spp., Enterococcushirae that transmucosaltranslocationofspecificbacteria(suchasLactobacillus The authorselucidated gutbacteriawithvancomycinpre-treatmentresultedinapoortherapeuticresponsecomparedtountreatedcontrols [9]. of gram-positive Moreover,environment. in agerm-free than inmiceraised gut microbiota in micewithhealthy to CTXwasgreater response depletion inbothbasicandclinicalstudies.Researchby Viaudwell characterised etal The interaction amongthe (CTX) immune system, (a microbiota andcyclophosphamide commonly usedalkylatingagent), has been and microbiotainduced T-cell activationisakeyinfacilitatingnovelanticancerimmunotherapy T-helpermyeloid cellactivationenhancestheactionof oxaliplatin; intraluminal theactionof cyclophosphamide; 17cellactivationenhance response inthehost[7–9]. motherapeutic and can occurarediverse.Bacterialtranslocation by whichimmunomodulation The mechanisms may cause systemic , increasedexposureto potential pathogenscanalsoprimethe adaptive immunesystem, augmenting che- triggeringbacterialtranslocation.Whilethis candamagethemucosalepithelium, regulate inflammation[5]. Chemotherapeutic tone and to settheimmune shown systems have been immune and adaptive and theinnate gut microbiota between constant interaction Modification of the immune responseby the microbiota playsa key response. role indetermining chemotherapeutic At the mucosal surface, Immunomodulation development ofpersonalisedandeffective anticancertherapy outcome [12]. chemotherapeutic impair may,of gutmicrobiota manipulation and Analysis for the a vitalcomponent therefore,become effects,side adverse cause structure canall community altered and xenometabolism with thehost.Immune interactions, relationship and community,of themicrobial aperturbation dysbiosis, Many ofthesefactorsgenerate therapy administered. disrupts thesymbiotic which and theeffect(such asantibiotics) medication use ofadjuvant intervention, and diet,surgical factors, suchhostenvironment ofthechemo- are highlyindividualised [10]. host microenvironment As the gut in synchrony andsymbiosiswith microbiota develops the host, its composition andfunctionality produce toxicsecondarymetabolites. They alsoexertanindirecteffectmetabolism throughmodificationof the on host-chemotherapeutic bacterial translocation[7–9]. chemotherapy-induced following and may medication chemotherapeutic The microbiotadirectlymetabolises organs and within lymphoid tabolism andalteredcommunitystructure[6]. Interaction withtheimmunesystemoccursbothintra-luminally Gut microbiota canmodulatethe host immune interactions,xenome response to through numerousmechanisms,including chemotherapy Host-chemotherapeutic-microbiota interaction system mayalsogeneratenovelchemotherapeuticapproaches and theimmune gut microbiota between of thecomplexinterplay of theirmicrobiota)[4].Increasedunderstanding genetic composition of anindividual’son theevaluation based regimens of chemotherapy and forpersonalisation interactions tic-microbiota (the microbiome efficacytherapeutic to enhance has thepotential side effects andabrogate host-chemotherapeu bymanipulating and toxicity)isrevealingtheintegralrolethatmicrobiotaplaysinefficacy andtoxicityofcancertreatment[3]. still. Inparticular, arelativelynovelareaofresearch,‘pharmacomicrobiomics’ (thestudyoftheeffect ofmicrobiotaondrugdisposition,action sequencing, metabolite profiling and bioinformatics algorithms is broadening our understanding of the interactions of the gut microbiota further ology. Whilethereismountingevidencethatthegutmicrobiomeplaysakeyroleincarcinogenesis[2],advancementofhigh-throughput and inflammatory pathways, exists in a delicate balance between symbiosis and pathogenesis and can influence many aspects of host physi- surface areaofmicrobialinteractionwiththehostimmunesystem[1]. This dynamicinterface,consistingofmultiplemetabolic,immunological The microbialcommensalsofthegastrointestinalsystem, the gutmicrobiota,outnumbercellsofhumanbody, andcomprisethelargest Introduction [11]. During thecourseofanticancertreatment,communitystructuregutmicrobiotaisaffected bymultiple [6]. . Further investigation demonstrated that administration of E.hirae that administration demonstrated [9, 14].Furtherinvestigation [5, 6]. 2 www.ecancer.org [9] usingamurinesarcomamodelshowedthat therapeutic [9, 13]. ecancer 2018,12:868 ) into mes- - -

Review commencing anticancertherapy reducing the effectcarbon-, of 5-FU. This the highlights importance ofwhen all host-microbe-druginteractions considering mayalsoaffectdamage. Concomitant activation. Forexample,itwasalsofoundthatmetformininhibitsbacterialone- pro- activation. Second,bacteriainfluencethehost DNAsupplying regulatorymetabolitesthat metabolic environment, augment 5-FU-induced RNAtwo distinct pathways. First,bacterial through fluoropyrimidines and pro-drug conversion B6 andB9enable and vitamins metabolism [19]. conducted byScott Further investigation of acytotoxiceffectfor thegeneration crucial was by monophosphate) to fluorouridine FUDR of 5-FUand (conversion metabolism effect andthe restorativeeffect ofFUDR.Geneticscreening acid (RNA) that ribonucleic used toelucidate were supplementation ofuracil response to differently.chemotherapeutics Nematodes fed with fertility,affectspecies be assessed.Itwasfoundthatbacterial could progeny to preventlive needed thedoseofchemotherapeutic the in led byGarcia-Gonzalez cancer,may bedue,not only to fluoropyrimidines, genetic polymorphismsbutalsoto variations ingut microbiota [10, 19]. Investigations interactions suggeststhat a modelfor symbiotic host-microbialthevariableclinicalresponseto the first-linechemotherapyfor colorectal metabolism [17, elegans nematode worm(C. 18]. elegans altering host-chemotherapeutic Recent researchusingtheCaenorhabditis The gutmicrobiotahasthepotentialtodirectlymetabolisechemotherapeuticdrugsandalsomodifyhostmetabolic milieu,indirectly Metabolism Bacteroides to CTLA-4display patients responsive Melanoma totheCTLA-4blockade. treated micedisplayednoresponse T cellreactionsspecificfor 4 couldcontrolestablishedMCA205sarcomasinmicewithhealthygut (CTLA-4, bacteria. However,ipilimumab) germ-free or - melanoma which target inhibitors, Immune checkpoint T-cellresults inpatientswithlungcanceroradvanced promising pathways, display regulatory administration ofCpGOGNwerereduced. This couldberestoredbyinoculationwith to intra-tumoural response immune adaptive the anticancer and production cytokine inflammatory cell mice, myeloid antibiotic-treated and DNA, whichbindto microbial in mice.Ingerm-free response immunological to stimulateatumour-eradicating TLR9, andcanbeinjected thus tumoureradication enhances theantitumoureffect by primingof of cells for myeloid oxaliplatin inflammatory cytokineproduction,and ROS release, enhancing microbiota that ahealthy It wasconcluded to oxaliplatin. poorly of ROS,alsorespond for theproduction critical an enzyme oxidase, NADPH by myeloidcells.Cybb-/-mice,deficientin species (ROS)generation for reactive-oxygen of genesresponsible agent) andtheexpression model. both DNAEL4 lymphomasreduced pre-treatmentofmicewithsubcutaneous Antibiotic (a DNAby oxaliplatin damage cross-linking efficacyon chemotherapeutic interaction cell myeloid and The impactofmicrobiota by Iidaetal investigated was progression-free survival patients withend-stagelungandovariancancer, a memory Th1 immune responsetowardsE. hirae in antibioticpre-treatedmicecouldalsorestoreresponsetoCTX[13]. studies. by clinical These findingshavebeencorroborated Among Tac micewasabletoslowbasaltumourgrowthenhancetheantitumoureffect ofanti-PD-L1[16]. to interact with dendriticcellsto activate T-cells andstimulatea protective anticancerresponse. Administration of are believed spp intheirgutflorawhich of Bifidobacterium seen inJaxmicewereduetothepresence response toanti-PD-L1 anticancer in zumab) wasimpaired Tacto Jaxmice. micecompared that theattenuatedbasaltumour growthandenhanced The authorsdetermined pembroli (anti-PD-L1, antibodies monoclonal celldeath1ligand-1 to antiprogrammed response growth. Furthermore,chemotherapeutic tumour did notconferincreased direction or byfaecaltransferfromJaxmice.Faecalintheopposite by eitherco-housing abrogated Farms (Tac) (Jax). Laboratory andJackson Tumoursin more aggressively grew Tacthis effectto Jaxmice and compared mice be could In anotherstudy, Sivan etal plays asignificantroleinenablingtheCTLA-4inducedantitumourresponse or adoptivetransferB.fragilis which were fed witheither were which C. elegans, [15]. It antibody againstcytotoxic was demonstratedthat treatment withasyntheticmonoclonal T-lymphocyte-associated Bacteriodes fragilis of Bacteriodes with theadministration salvaged be could mice in germ-free to ipilimumab reaction species;therapeutic [8]. Aeffect similar of synthetic mimics (CpG OGN).CpGOGNare with CpGoligodeoxynucleotides wasobserved et al [6, 10,11, 14, 17]. [16] observeddifferentialsimilar micesourcedfromtwosuppliers—Taconic growthingenetically melanoma -specific T cells. between that theinteraction This indicates [19] testedtheefficacy(FUDR) (5-FU) and5-fluoro-2’-deoxyuridine ofcamptothecin (CPT),5-fluorouracil [10]. E. coliorComamonas et al using three-way high-throughput screens verifiedthat [10] bacteria alterthe effectsusing three-wayhigh-throughput of bacteria. nematode impair and division cell inhibit As fluoropyrimidines E. coli were two orders of magnitude moresensitiveto the sterilising 3 www.ecancer.org [4]. Alistipes shahii Bacteriodes was foundto be apositivepredictorof [8]. species and the immune system speciesandtheimmune in a murine lymphoma a murine [8], in ecancer Bifidobacterium spp. 2018,12:868 ) as to -

Review to reduceCTLA-4blockadeinducedcolitisinanantibiotic-treated mousemodel dance oftheBacteriodetes 2 administration 2 ligand receptor treated micehavebeenshownto small bowelinjury,be moresusceptibleto methotrexate-induced which canbesalvagedwith Toll-like interact, via Toll-likeFor example,antibiotic- and promotinghealing. inflammation receptors, withtheinnateimmunesystem, regulating Effortsinjury. to preservecommunitystructurecould,therefore,protectagainstchemotherapeutic It has beenshownthat healthy microbiota colitis, bacterialtranslocationandinfection trophic factorforenterocytes. flammatory propertiesandanessential the riskof increases barrier to theintestinal The resultantdamage with antiin fatty acid short chain of butyrate—a the production may reduce bacteria of anaerobic in the abundance and adecrease gens the prevalenceof potentially pathogenicEscherichia for nonHodgkin’schemotherapy dose of commensal the abundance reduces dramatically lymphoma and a296-folddecreaseinStreptococci with a13-folddecreaseinprotectiveanaerobes were associated this equilibrium disrupting and healthofgutmicrobiota, capillary network, a reductioninsurfaceareaandpoorperistalsis[29, 30]. Administration ofcandamagethediversity chemotherapeutics by analysis ofgerm-freemice,whichdisplaythinvilli,areduced maintain thestructureandfunctionofgutmucosalbarrierisrevealed crypts [28]. intestinal within of protectiveantimicrobial host production have beenshowntoinduce to of microbiota The importance immunotherapy,into PD-1inhibitor lows aninvestigation which ishighlyeffectivethe murine inonlyasmallsubsetofpatients.Following priorto to therapy.treatment andto chemotherapy personalise A key exampleoftranslationfrom fol- basic researchto clinical application response patient to predict the potential holds analysis microbiome intestinal increases, of pharmacomicrobiomics As ourunderstanding Translation towardclinicalpractice Commensal microbiotacanprime and modulatehostimmunityto prevent pathogenovergrowth.Indeed,Bacteroides of intestinalhealth[27]. Bacterial communitystructureisakeydriverofsymbiosisbetweenthehostandmicrobiotamaintenance Community structure administration with antibiotic of gutmicrobiota by depletion levels ofBVUandcouldbeabrogated Indeed,inarodentmodel,circulating from sorivudine. BVU for producing that themicrobiota, ratherthanhostenzymes,isresponsible revealed uracil]. Furtherinvestigation (2-boromovinyl) metabolite, BVU[(E)-5- deactivates 5-FU)byasorivudine (which dehydrogenase dihydropyramidine of hepatic by inactivation caused 16 deathsovera40dayperiod levels of5-FU,causing and 5-FUledtotoxiccirculating sorivudine tration oftheantiviral can havefatalconsequences. metabolism of gutmicrobiota understanding Inadequate co-adminis in Japan,when This wasobserved inhibitors of bacterial-specific pave thewayfordevelopment counterparts, which to theirhuman motifsrelative unique possess ß-glucuronidases have beenshowntobeeffectiveactivity andmucositis[22, 23]. ß-glucuronidase Furthermore, bacterial of bacterial inthesuppression and lowdosesofamoxapine of themicrobiotamayprovidenoveltherapeuticoptions.Ciprofloxacin mucositis whilemanipulation induced may,characterisation transporters [20].Microbiome membrane idases andglucuronide therefore,identifypatientsatriskofirinotecan- that differentialdemonstrated ß-glucuron bacterial of specific the presence with correlated volunteers of SN-38Gbyhealthy reactivation isoforms, which differThere arenumerousbacterialß-glucuronidase in theirsubstratepharmacokinetics However,within the gut bacterial ß-glucuronidases lumen canreactivateSN-38Gto its active, enterotoxic form, causing mucositis[20]. SN-38G, whichisexcretedintothegutwithbile. producing of topoisomerase1.It is laterdeactivatedbyhepaticglucuronidation, inhibitor diarrhoea inupto mucositis causessevere,dose-limiting30%of patients [20]. Irinocetan isactivatedbyhydrolysisto form SN-38, an Microbial metabolismmaycausesideeffects severe enoughtonecessitatecessationofchemotherapy. For example,irinotecan-induced [22–24]. [18, 26]. phylum was associated with resistancetocolitis. wasassociated phylum of Bacteriodales Administration [34]. that abun revealed therapy anti-CTLA-4 taking in patients microbiome of theintestinal An analysis [31]. . Chemotherapeutic-induced dysbiosis reduces colonisation resistance topatho- dysbiosis reducescolonisation [33]. Chemotherapeutic-induced . In a rat model, methotrexate-induced mucositis and reduced villous length villous and reduced mucositis methotrexate-induced [31]. Inaratmodel, 4 www.ecancer.org [4, 35]. Faecalibacterium [32]. In humans,1weekof high- [21]. Guthrie et al has subsequently been shown hassubsequently ecancer with an increase in an increase with and Lactobacillus 2018,12:868 . This was [25]. This [20] recently - - - -

Review response. Metagenomic analysis of revealed anabundance response. Metagenomicanalysis chemotherapeutic patients toagerm-freemurinemodelwasshownameliorate fromresponding transplantation faecal microbial while 36–38] 50% increaseinmeansurvivaltime tested molysin E (an antitumourtoxin). density.control of system This createdapulsatiledelivery microbial population with simultaneous When Din toan protein-2 (BMP-2). in vitromodelof When exposed colon cancer,cell line. the bacteriuminducedapoptosisofadenocarcinoma ing. of bacteriafordeliverychemotherapy,Innovative possibilitiesforthegeneticengineering or asvectorsforgenetictherapy, are emerg- Novel chemotherapeutics transplantation totacklesteroid-resistantGVHDinfourpatientshaveshownpromisingresults of the colon,impairmentof tive mucouslining and increasedincidenceof the intestinalbarrier GVHD [44]. Early studiesof faecal microbiota in micedemonstratedthat antibiotic administrationresultedinanincreaseAkkermansiamucinophilia mortality at5years. (GVHD)-related graft-versus-host disease with increased treatment wasassociated during administration The analysis dent ofknownpredictorsandco-morbidities Low microbialdiversitywasassociatedwitha31%reductionin3-yearsurvival comparedtohighdiversity,plantation (allo-HSCT). indepen into low-,intermediate-or high-diversity cohortsbasedonfaecal16SrRNA stem analysis shortlyafterhaematopoieticcelltrans- allogenic treatment mayalsobeusedtopredictprognosis. chemotherapeutic Dysbiosis of the gutmicrobiotafollowing Taur et al microbial manipulationbetweenenhancementofchemotherapeuticeffect andreductionoftoxicity[43]. more than30%ofpatients,andcanbesevereenoughto prevent therapeuticdoseadministration,acompromisemayneedto be madein amongstgerm-freemice. was lower hyperalgesia induced mechanical For example, whilethe response to may microbiota enhance chemotherapeutic oxaliplatin effects, aswelladvantageous As microbiotamayhavedeleterious may notbepossible. manipulation the perfectbalanceofmicrobial faecal microbiotatransplantationmayalsoholdtherapeuticpotential with manipulation of systemicinfection[41].Ecological that theymayreducetheincidence have alsosuggested chemotherapy tion during mucositis inrodent models of irinocetan-induced the incidence toreduce shown has been administration VSL#3 probiotic and therapies activity) [39].Useofbothantibiotic or biological to exertimmunological products microbial pre-biotic therapy(compoundsadministeredto encourage the functions of certain microbiota)andpost-biotictherapy(useof nonviable micro-organisms), of living (administration therapy probiotic species), bacterial specific (targeting therapy antibiotic selective include These of microbiota. Variousligent drugselectionormanipulation measuresmaybeemployedpriorto, during andafter drug administration. Although different bacteria wereidentified,this research holdspromisefor optimisation of chemotherapeutic efficacy, either throughintel- antitumour effect ofPD-1blockadeintherecipientmice the restored mice into germ-free responders from human transplantation microbial faecal and patients in responding to bemoreabundant longum patients. Bifidobacterium stool samplesfrommetastaticmelanoma immunity, which couldbetransferredto germ-free miceusingfaecaltransplantation Ruminococcaceae PD-1 immunotherapy.patients undergoing ofmelanoma the microbiomes of diversity andrelativeabundance alpha higher Significantly to PD-1blockade ingerm-freemicerestoredtheresponse of thebacterium supplementation by Zitvogeletal conducted research to cause the bacterium to lyse synchronously and release Hae- release and to lysesynchronously the bacterium in E.colitocause present feedback loops sensing et al[48]usedthequorum In astudybyPillai on a mouse model of hepatic colorectal metastases, oral administration of the bacterium, in combination with 5-FU,ledtoa ofthebacterium,incombination metastases, oraladministration colorectal in vivoonamousemodelofhepatic . Zitvogeletal family were observed in responding patients. Immune profiling of patients revealed enhanced systemic and antitumour systemic and enhanced of patientsrevealed patients. Immuneprofiling in responding observed familywere [39] et al found that abnormal gut microbiome composition was associated with failure to respond to anti-PD-1 therapy,to anti-PD-1 to respond withfailure was associated composition gut microbiome found thatabnormal [47], was genetically modified to enable of atumoursuppressor,excretion toenable modified genetically E.coli was morphogenic bone human [43]. Shen et al [48]. This protective effectThis protective refaunation. gut microbial waslostfollowing affectshyperalgesia As mechanical and Sivan [39] and [12]. Furthermore, astudyof857casesallo-HSCTthat broad-spectrum antibiotic revealed demonstrated that the incidence of oxaliplatin-induced mechanical hyperalgesia mechanical [43] of demonstrated that oxaliplatin-induced the incidence et al [37]. (described earlier), three clinical studies have recently emerged [4,16, emerged recently have studies three clinical earlier), [16] (described Akkermansia muciniphila 5 www.ecancer.org [42]. , Collinsella aerofaciens Collinsella associated positivelywithclinicalresponseandoral [38]. Finally, Gajewski et al [23, 40].Variousadministra - studies onprobiotic [8], they may also engenderchemotherapy- [45, 46]. [36]. Gopalakrishnan andEnterococcusfaeciumwerefound and associatedlossof the protec- ecancer [37] [12] divided patients et al examined baseline 2018,12:868 [38] examined -

Review References The authorsdeclarenoconflictsofinterest. Conflicts ofinterest ability, itissurelyworththeeffort. lenge efficacyof chemotherapeutic a perfectbalance to achieve of thegutmicrobiota effectsof side reduction and chal- a significant presents the role of gut microbiota andtheirroleinchemotherapywillrequirea dedicated andinnovativesystems approach.Manipulation of understanding a comprehensive benefit andharm.Obtaining has thecapacityforbothclinical The functionaldiversityofthemicrobiota outcome [31–34]. and mucosaldestruction,isassociated withadverse which promotesinflammation administration, disrupted bychemotherapeutic can evenprovefatal that and neuropathy toxicity suchasmucositis to drug contributions has revealed metabolism of gutmicrobial understanding increased effective arehighly at present which foronlyasmallsubsetofpatients[36–38].However,beneficial. are notalways gutmicrobes An model patient cohortsandtransfer of chemotherapeutic responsehasbeenachievedwithadministrationof human faecalsamplesto a murine amongst survival havebeenidentified associated withprogression-free research. Specificmicrobials withclinical cessfully correlated response has chemotherapeutic been clearlyshowninanimalmodels[8, 9, 13, 14, 36–38]. Furthermore, theseresultshavebeensuc- as hostimmunity,diet [6]. and environment , concomitant chemotherapeutics, to augmentthe of gutmicrobiota The ability cancer therapy,During factors, such multiple between by complexinteractions is adynamicstructure,influenced thegutmicrobiota Conclusion

8. 5. 4. 3. 1. 7. 6. 2. tumor microenvironmentScience N, Dzutsev Iida Stewart CA,etal(2013) A, and Biol Med E and Perez-Chanona TrinchieriG (2016) ence 3501079–1084 Vétizou M, Pitt R, etal(2015)AnticancerimmunotherapybyCTLA-4blockaderelieson JM, the gut and Daillère microbiota microbiomics CurrPharmacogenomicsPersMed Rizkallah MR, Saad R, and Aziz RK (2010) The Human Microbiome Project, personalized medicine and the birth of - pharmaco PMID: 24132111 PMCID:3986062 Cell R, FuchsS,andMiloR(2016) Sender Erdman SE and Poutahidis SE and Erdman T (2017) Gastroenterol Hepatol JL, WilsonID,and Alexander Teare J,etal(2017)Gut microbiota modulation of chemotherapyefficacyand toxicity org/10.1016/j.coi.2016.01.003 C (2013) Jobin RF and Schwabe [43]. However,efficacy todeliveraneweraofcancertreatment,improving with thepotentialofpharmacomicrobiomics andtoler- [36–38]. These findingshavetremendousclinicalpotential,particularlyinthe field of(suchanti-PD-L1), novel immunotherapeutics 164337–340 10528–34https://doi.org/10.1016/j.freeradbiomed.2016.11.013 [22, 23, 25, 26, 43]. of The bacterial communitystructure delicate equilibrium and host-microbiotainteractionsis also https://doi.org/10.1016/j.cell.2016.01.013 https://doi.org/10.1126/science.aad1329 14356–365 PMID: https://doi.org/10.1038/nrgastro.2017.20 342967–970 Gut microbiota modulate host immune cells in cancer development andgrowth host immunecellsincancer Gut microbiotamodulate 26820225 Are wereallyvastlyoutnumbered? revisiting theratioofbacterialtohostcellsinhumans The microbiomeandcancer The roleofmicrobiotaincancertherapy PMCID:4801762 https://doi.org/10.1126/science.1240527 Commensal bacteria control cancer response to therapy by modulating the to therapy response control cancer bacteria Commensal 8182–193 PMID: PMID: https://doi.org/10.2174/187569210792246326 6 www.ecancer.org 26824647 26541610

Nat RevCancer PMID: PMCID:4721659 28270698 PMID:

Curr OpinImmunol 13 800 24264989 https://doi.org/10.1038/nrc3610 ecancer 39 75–81 2018,12:868

Free Radic https://doi. Nat Rev Sci-

Review 25. 24. 23. 22. 21. 20. 19. 18. 12. 10. 17. 16. 15. 14. 13.

11. 9. dropyrimidine dehydrogenase Diasio RB(1998)Sorivudine and 5-fluorouracil; A clinically significant drug-drug interaction due to inhibition of dihy- 831–835 WallaceBD, Wang H,andLaneKT, etal(2010)Alleviatingcancerdrugtoxicitybyinhibiting a bacterialenzyme jugation oftheirinotecanmetaboliteSN-38-G T,Kodawara T,Higashi Y,Negoro and PMID: 24780296 PMCID: 1873978 inhibitors for alleviating cancer drug toxicity R, Liu Kong T,Zhu X,etal(2014) and PMCID: 4575908 the alleviation of cancer drug toxicity Wallace BD, Roberts AB, and PolletRM, NPJ BiofilmsMicrobiomes Guthrie L, Gupta S, and DailyJ, chemotherapeutics Cell García-González AP, Ritter AD, and Shrestha S, Drug MetabDispos Klaassen CDandCuiJY (2015) Review:mechanismsof how the intestinal microbiota alters theeffectsof drugs and bile acids dmd.115.063867 hematopoietic stem celltransplantation Taur Y, M-A,etal(2014)Theeffectsofintestinal tract bacterialdiversityon JenqRR,andPerales mortality following allogeneic of theelderlyProcNatl Acad Sci1084586–4591 O, etal(2011)Sullivan S, and MJ, Cusack Claesson Composition, variability, andtemporal stabilityoftheintestinalmicrobiota Cell Scott TA,P,Norvaisas LM, and Quintaneiro etal(2017) Kim D (2015) Kim D(2015) PD-L1 efficacy Sivan A, CorralesL,andHubertN,etal(2015) aaa8172 Sharma P and Allison JP (2015) The future of immune checkpoint therapy 356–365 Viaud S,Viaud S,andSaccheriF, etal(2016)Two bugs a NODawayfromimproving cancer therapyefficacy PMID: 27717798 phamide-induced therapeutic immunomodulatory effects Daillère R, Vétizou M, and Waldschmitt N, PMCID: 4133489 phosphamide Viaud S, Saccheri F, and MignotG, 169442–456.e18 PMID: https://doi.org/10.1126/science.1191175 PMID: https://doi.org/10.1126/science.1240537 Gut microbiota-mediated drug-antibiotic interactions Science Science 25838373 PMID: PMCID:4079752 431505–1521 https://doi.org/10.1016/j.cell.2017.03.040 342(6161)971–976 3501084–1089 25926432 169431–441.e8 327https://doi.org/10.1038/s41522-017-0034-1 et al (2017) Human microbiome signatures of differential colorectal cancer Br J Clin Pharmacol Br JClin https://doi.org/10.1124/dmd.115.065698 et al (2013) The intestinal microbiota modulates the anticancer immune effects of cyclo- et al The (2016) inhibitory effect of ciprofloxacin on the β-glucuronidase-mediated decon- Old drug new use—amoxapine and its metabolites as potent bacterial β-glucuronidase bacterial potent as metabolites its and use—amoxapine new drug Old https://doi.org/10.1126/science.aac4255 Chem Biol et al (2016) Enterococcus hirae and barnesiella intestinihominis facilitate cyclophos https://doi.org/10.1016/j.cell.2017.03.046 tutr ad niiin f irboe -lcrndss seta to essential β-glucuronidases microbiome of inhibition and et al (2015) Structure

https://doi.org/10.1126/science.1240537 Blood Commensal Bifidobacteriumpromotesantitumorimmunityandfacilitatesanti- BasicClinPharmacolToxicol et al (2017) Bacterialmetabolismaffectsthe C. elegans responseto cancer Clin CancerRes https://doi.org/10.1073/pnas.1000097107

124 1174–1182 https://doi.org/10.1182/blood-2014-02-554725 1238–1249 https://doi.org/10.1016/j.chembiol.2015.08.005 22 1238–1249 Host-microbe co-metabolism dictates cancer drug efficacy in C.elegans drug efficacy co-metabolism dictatescancer Host-microbe

21051639 46 1–4

7 www.ecancer.org Immunity https://doi.org/10.1046/j.1365-2125.1998.00050.x PMCID:3110694 20 3521–3530 Drug MetabDispos 45 931–943 PMID: PMID: 118 Science PMID: 29104759 26261286 333–337 PMCID:5484065 https://doi.org/10.1158/1078-0432.CCR-14-0395 PMID: https://doi.org/10.1016/j.immuni.2016.09.009 https://doi.org/10.1016/j.immuni.2016.09.009

26541606 348 56–61 https://doi.org/10.1126/science.

43(10) 1581–1589 24264990 PMCID:5665930 PMCID:4576672 https://doi.org/10.1111/bcpt.12511 PMCID:4873287 PMCID:4048947 ecancer https://doi.org/10.1124/ 24939656 PMID:24939656 PMID: PMID:9690942 2018,12:868

Immunity Science 26364932 26364932

330 45 -

Review 38. 37. 39. 36. 33. 32. 41. 40. 35. 34. 31. 30. 26. 27. 29. 28. melanoma patientsScience V,Gopalakrishnan CN,andNeziL,etal(2018) Spencer melanoma patientsScience Matson V, FesslerJ,andBaoR,etal(2018)Thecommensalmicrobiomeisassociatedwith anti-PD-1 efficacyin metastatic Zitvogel L, Galluzzi L, and Viaud S, epithelial tumors L, etal(2018) E, andDerosa Routy B,LeChatelier org/10.1007/s00248-013-0355-4 during high-dose chemotherapyasconditioning regimen forbone marrowtransplantation Montassier E, Batard E, and MassartS, s00520-014-2487-6 chemotherapy-induced gastrointestinalmucositisin a ratmodel Fijlstra M,FerdousandKoning AM, etal(2015) ing chemotherapyforpediatricmalignancies Wada M, Nagata S, and SaitoM, loss CancerBiolTher Bowen J, Stringer A, and GibsonR, doi.org/10.1126/scitranslmed.3010473 point-blockade-induced colitis MK, andRenB, Dubin K, Callahan jimmunol.1402481 signaling modulates sideeffectsofanticancertherapyin the smallintestine Frank M, EM, Hennenberg andEyking A, et al (2015)Europe PMC Funders Group Europe PMC Funders Author Manuscripts TLR Clin InfectDis49262–270 receiving prophylaxis leads toarelativeincreaseofcolonization with potentially in the gut van VlietMJ, Tissing WJE, and DunCAJ,etal(2009)Chemotherapytreatmentin pediatric patientswith acute myeloid leukemia PMID: 21606592 inflammation in mice through an EGFR-dependent mechanism Yan F, Cao H, and Cover TL, 8836–8847 35–43 blood concentration of5-(E)-(2-bromovinyl)uracilthatincreasesthelevelandtoxicity5-fluorouracil H, Kinouchi Nakayama T, andKataokaK,etal(1997)Intestinalanaerobicbacteriahydrolysesorivudine, producing thehigh Chow J, Lee SM, and Shen J, LeeSM,and Chow Y, etal(2010) Jandhyala SM, Jandhyala TalukdarC, etal(2015)Roleof the normalgut R,andSubramanyam microbiota Science Cash HL,WhithamCV, and Behrendt CL,et al (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin org/10.1016/B978-0-12-381300-8.00008-3 https://doi.org/10.1097/00008571-199702000-00005 3131126–1130 https://doi.org/10.1126/science.1127119 PMID: https://doi.org/10.3748/wjg.v21.i29.8787 PMCID:3104743 Science PMID: 6(9)1449–1454 25589072 35991–97https://doi.org/10.1126/science.aan3706 https://doi.org/10.1086/599346 35997–103 359104–108 et al (2011) PMID: NatCommun et al (2010) Effectsof the enteral administration of Bifidobacterium breve on patients undergo- et al VSL#3 (2007) Probiotic treatment reduceschemotherapy-induced diarrhoea and weight et al Cancer and (2015) the gut microbiota: An unexpected link PMCID:4338614 et al(2016)Intestinal microbiome analysesidentify melanoma patientsatriskforcheck- https://doi.org/10.4161/cbt.6.9.4622 24402367 et al (2014) 16SrRNA gene pyrosequencing reveals shift in patient faecal microbiota https://doi.org/10.1126/science.aan4236 Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal Host–bacterial symbiosis inhealthanddisease Host–bacterial https://doi.org/10.1126/science.aao3290 710391PMID:26837003 SupportCareCancer Gut microbiome influences efficacy of PD-1-based immunotherapy against immunotherapy of PD-1-based Gut microbiomeinfluencesefficacy Substantial decreases in thenumberanddiversity ofmicrobiotaduring Substantial decreases PMID: Gut microbiomemodulatesresponsetoanti-PD-1immunotherapy in PMID: 8 www.ecancer.org 19514856 9110360 J ClinInvest 18751–759 Support CareCancer 16931762 PMCID:4740747 PMID: PMCID:2716667 J Immunol 17881902 121 2242–2253 https://doi.org/10.1007/s00520-009-0711-6 PMID: 29302014

194 1983–1995 23 1513–1522 Adv Immunol Microb Ecol https://doi.org/10.1172/JCI44031 Sci Transl Med World JGastroenterol ecancer 107 243–274 https://doi.org/10.1007/ https://doi.org/10.4049/ 67 690–699 Pharmacogenetics 2018,12:868 1–10 7 1–10 https://doi. https://doi. https://

21 7

Review 45. 48. 47. 46. 44. 43. 42. graft-versus-host disease ofthegut graft-versus-host K, Fujioka Kakihana Y, and SudaW, org/10.1126/scitranslmed.aaf2311 PMID: Din MO, Danino Din T,Prindle and A, etal(2016) cer: aproof-of-conceptstudy S, Pillai R, etal(2012)E.coli-Produced BMP-2 asachemopreventivestrategyforcolon S, andSomasundaram can- Al-lahham graft-versus-host disease Staffas A, BurgosM,andBrinkMRMVan Den(2017) PMCID: 5085256 allogeneic hematopoietic stem cell transplantation in human patients and mice Shono Y, DocampoMD,andPeledJU,etal(2016)IncreasedGVHD-relatedmortalitywith broad-spectrum antibiotic use after 20 1213https://doi.org/10.1038/nn.4606 Shen S, Lim G, and You Z, https://doi.org/10.1136/gutjnl-2015-309990 JR, Marchesi Adams DH,andFavaF, etal(2016) doi.org/10.1038/nature18930 Blood et al(2017)Gut microbiota is criticalfortheinduction of chemotherapy-induced pain PMID: Gastroenterol ResPract 129927–934 27437587 et al(2016)Fecalmicrobiota transplantation for patientswith steroid-resistant acute PMID: 27194729 PMCID:4752653 Blood Synchronized cycles of bacteriallysisforinvivodelivery Synchronized cycles PMCID:5048415 28714953 https://doi.org/10.1182/blood-2016-09-691394

2083–2088 https://doi.org/10.1182/blood-2016-05-717652128 2083–2088 PMCID:4991773 The gutmicrobiotaandhosthealth:anewclinicalfrontier The intestinalmicrobiotainallogeneichematopoieticcelltransplantand 2012 PMCID:5575957 895462 9 www.ecancer.org https://doi.org/10.1155/2012/895462 Sci Transl Med PMCID:5324712 8 339ra71–339ra71 Nature ecancer PMID:27461930 81–85 https:// 536 81–85 Gut 2018,12:868 Nat Neurosci 65 330–339 https://doi.

Review