Article

Gut microbiota: Its role in diabetes and obesity

Neil Munro

Citation: Munro N (2016) Gut The is a community of microogranisms that live in the gut and intestinal microbiota: Its role in diabetes tract. The microbiota consists of , and eukarya, as well as , but is and obesity. Diabetes & Primary Care 18: 168–73 predominantly populated by anaerobic bacteria. Relationships between gut microbiota constituents and a wide range of human conditions such as enterocolitis, rheumatoid Article points arthritis, some cancers, type 1 and type 2 diabetes, and obesity have been postulated. 1. The role of the gut microbiota This article covers the essentials of the gut microbiota as well as the evidence for its role in certain disease progressions in diabetes and obesity. has been postulated, particularly its role in diabetes and obesity. he human gut microbiota is “an ecological Identifying microbiota constituents 2. There is much greater community of commensal, symbiotic and Until relatively recently, bacteria could only be genetic diversity between pathogenic micro-organisms that literally identified by direct microscopy and culture. people’s gut microbiota than T share our body space” (Lederberg and McCray, This proved particularly problematic with most between their . 2001). It is made up of between 10 and 100 trillion anaerobic commensal gut (Ursell et al, 3. Improved understanding of the mechanisms by which the micro-organisms (with a mass weight of 1.5 kg) 2012). It has only been in recent years that human microbiota contributes and is found in the distal intestine (Allin et al, advances in gene sequencing and analytical to the development of 2015). The microbial community acts in concert techniques have made it possible to define and type 1 and type 2 diabetes with the body to provide important functions classify microbial DNA from faecal collections offers the potential for novel interventions. that the body cannot provide alone. The gut – generally considered to reflect the distal bowel microbiota is involved in the following: microbiota (Kuczynski et al, 2012). Two detection Key words l It is a key component of the . methods are currently employed; targeted 16S – Bacteria l Protection against . ribosomal RNA gene sequencing and un-targeted – Gut l Regulation of intestinal hormone secretion. whole- shotgun sequencing (otherwise – Microbiota l Modulation of gastrointestinal nerve known as metagenomic sequencing; Weinstock, function. 2012). The former generates information about l Synthesis of vitamin K, folate and B12. the bacteria themselves (i.e. types, numbers and l Generation of short-chain fatty acids through relationships), while the latter provides a picture of fermentation of non-digestible . the collective genome of the gut microbiota (i.e. the l The breakdown of toxins and medications. gut ). Gene diversity in the Interest in the association between constituent dwarfs that of the entire human genome. The elements of the human microbiota and disease MetaHIT Consortium found 3.3 million non- dates back to the 1680s around the time of the redundant genes in the microbiome compared to birth of the study of itself (Dobell, 22 000 genes in the human genome (Qin et al, 1920). In his research into the diversity of the 2010). More recently a microbial gene catalogue human microbiota, of 9.9 million genes from European, Chinese and (1684) compared his own oral and faecal American samples has been published (Li et al, microbiota and noticed significant differences 2014). Importantly, the genetic diversity of the Author in microbes between these different sources. He microbiome between individuals is far greater Neil Munro is Visiting Professor went on to examine and compare microbiota than that of the human genome. People are 99.9% in Primary Care Diabetes, from others in good health, as well as those identical to each other in terms of their human Department of Clinical and Experimental Medicine, with established disease, also noting significant genome but can be 80–90% different from each University of Surrey. differences between sample sites. other in terms of their gut microbiome (Turnbaugh

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et al, 2009). In an age of personalised medicine, age when immune-related changes in the gut Page points the variation within the microbiome presents a microbiota can occur (Arumugam et al, 2011). 1. In an age of personalised potentially useful avenue for future interventions medicine, the variation in disease processes. What is the relationship between the within the microbiome from person to person presents a microbiota and diabetes? potentially useful avenue for Does the microbiota change throughout Relationships between gut microbiota constituents future interventions in disease life? and human conditions, including enterocolitis, processes. Birth and childhood rheumatoid arthritis, muscular dystrophy, multiple 2. The microbiota and its bacterial composition is influenced by The relative bacterial composition of the microbiota sclerosis, some cancers and a range of psychiatric several factors throughout life. is influenced by several factors throughout life and disorders, have been postulated. Of key interest to There are variations from birth in childhood in particular. the endocrine world is the possible link with type 1 to adulthood. Babies delivered vaginally develop microbial diabetes, type 2 diabetes and obesity. 3. The mechanisms through which the microbiota may precipitate populations within 20 minutes of birth, mirroring type 1 diabetes in susceptible those of their mother’s vagina and rectum What is the relationship between the individuals relate to alterations (Lactobacillus, Prevotella or Sneathia), while the microbiota and type 1 diabetes? in intestinal permeability and microbiota of babies born by Caesarian section are The involvement of the microbiota in the modification of intestinal immunity. derived from microbes on the hands that touch development of type 1 diabetes in animals was first and hold the baby after birth (Staphylococcus, proposed in 1987 by Suzuki et al. A recent Finnish and Propionibacterium; human study used age and HLA-DQ genotype to Domininguez-Bello et al, 2010). match four children who went on to develop type 1 The gut microbiota of infants tends to be diabetes with four children who remained healthy. narrow and unstable. Breast feeding, formula Comparison of their revealed a lesser milk, antibiotic treatment, illness and travel can diversity and stability of faecal microbiota in the all contribute to the changeable milieu of the first year of life in children in the former group microbiota in the young (Koenig et al, 2011). After (Giongo et al, 2011). The children who developed the age of 3 years, diet, including variations in solid type 1 diabetes were subsequently found to have food ingestion, and illness are the predominant a decreased ratio of Firmicutes versus determinants of the microbiota (Power et al, 2014). (de Goffau et al, 2013). Other studies have also By the age of 7 years, Firmucites and Bacteroidetes reported a greater proportion of Bacteroidetes in comprise about 90% of the islet body-positive children than in auto-antibody- present in a child’s microbiota, with the remaining negative children (de Goffau et al, 2014). 10% being made up by Tericutes, Cyanocobacteria The mechanisms through which the microbiota and Proteobacteria. The microbiota becomes more may precipitate type 1 diabetes in susceptible stable at this stage and begins to resemble that of individuals relate to alterations in intestinal adults (Dominguez-Bello et al, 2011). permeability and modification of intestinal immunity. In the healthy state, the intestinal Adulthood epithelium prevents food antigens, as well as In healthy adults, the microbiota is stable and is commensal and pathogenic bacteria, from inducing related to long-term diet patterns. Three enterotypes systemic immune responses (Mazmanian et al, are found in adults globally: Bacteroides (the 2005). predominant class in the phylum Bacteroidetes), In type 1 diabetes, the development of a more Prevotella and Ruminococcus (Wu et al, 2011). All permeable intestinal barrier (a key component of three can be linked to diet and living conditions. For human defence mechanisms) may be attributable instance, Bacteroides are found in those with high to metabolites of gut microbiota, as much as animal protein and saturated fat intake (western to any direct action of microbes themselves. diet), while Prevotella, by contrast, are found in Children with type 1 diabetes have low numbers those in agricultural and vegetarian communities of Bifidobacteria, which are lactate-producing where high consumption of carbohydrates and microorganisms (de Goffau et al, 2013). Butyrate, sugars is the norm, and remain so until older a short-chain fatty acid, is derived from lactate and

Diabetes & Primary Care Vol 18 No 4 2016 169 Nutrients 2015, 7, page–page

5. Microbiota: Molecular Mechanisms in T1D To explain the pathways and the impact of T1D‐associated in the metabolism, it is necessary to study the microbiota structural dynamics as an integral organ [52]. Understanding that the gut microbiota is an organ will make it possible to integrate its relationship with T1D as a key for designing new therapies to prevent and/or improve the T1D control. Dietary components provide different substrates that may result in several products during the fermentation processes. Changes in the microbiotal structure due to diet modifications are because some of the bacterial communities are “genetically better equipped” to metabolize those substrates. Moreover, the same substrate can be used in different pathways according to the type of bacteria that are colonizing the intestinal niche, or in relation to its abundance and available frequency [13]. An example of the former statement is lactate. This substrate can be transformed into butyrate or, in others, short chain fatty acids (SCFA) such as acetate, succinate, and propionate during its anaerobic bacterial fermentation in the gut, depending on the type of microbiota [50]. The lactate model appears to be the strongest possible explanation for understanding the link between T1D and dysbiosis (Figure 1). According to this model, the presence of lactic acid‐ and butyrate‐producing bacteria such as Prevotella and Akkermansia helps to maintain a healthy Gut microbiota: Its roleepithelium. in diabetes Thisand obesity is because butyrate contributes to mucin synthesis and to the assembly of tight junctions [53]. These bacteria were common in the microbiota of healthy children around the world [9–12,15,50]. In contrast, when microorganisms such as Bacteroides and Veillonella are harbored in abundance, this substrate follows the pathway to succinate, acetate, and propionate. These products Nutrientscompromise2015, 7 ,mucin 9171–9184 synthesis and increase paracellular permeability by altering the tight junctions [50].

Page points 1. The microbiota may precipitate type 1 diabetes in susceptible individuals through alterations to intestinal permeability and modification of intestinal immunity. 2. Improved understanding of the mechanisms by which the human microbiota contributes to the development of type 1 diabetes in genetically susceptible individuals offers the potential for novel interventions in the prevention or amelioration of type 1 diabetes.

FigureFigureFigure 1.1. Diet 1.Diet Diet and and and microbiota-associatedmicrobiota microbiota associated associated mechanisms mechanisms mechanisms in autoimmunity in and autoimmunity autoimmunity type 1 diabetes development andand typetype (Mejía-León 1 diabetes diabetes and Calderón de la Barca, 2015). (T1D)(T1D) development. development. is a potent anti-inflammatory agent promoting cytokines. Lastly, bacteria that permeate a “leaky” In addition, butyrate may contribute to maintaining the anti‐inflammatory response in the In addition,gut barrier butyrate function mayby ensuring contribute tight junctions to maintaining intestine may the cause anti-inflammatory further response and in the healthy gutbetween by inhibiting epithelial cells.the activation Its relative deficiency of NF‐κ B,may signaling beta-cell throughdestruction G (Figure protein 1). ‐coupled receptors, and healthy gut by inhibiting the activation of NF-κB, signaling through G protein-coupled receptors, leading to thecontribute modulation to the increased of antioxidant intestinal permeability defense systems, Improved nitric understanding oxide production, of the mechanismsand the expression and leading to the modulation of antioxidant defense systems, nitric oxide production, and the of inflammatoryseen in children cytokines developing [28,36]. type 1High diabetes‐fiber (Hague diets by have which been the humanassociated microbiota with contributes a decreased to risk of expressionet of al, inflammatory 1996). cytokines [28,36]. High-fiberthe development diets have of beentype 1 associated diabetes in genetically with a decreased inflammatory immune‐related diseases. However, it is unknown whether this effect is due to the risk of inflammatoryIntestinal immunity immune-related is significantly diseases. impaired However, in susceptible it is individuals unknown offers whether the potential this for effect novel is due to butyrate itself or to the associated microbial profile [28]. Butyrate also enhances extra‐thymic the butyratetype itself 1 diabetes. or to Activation the associated of immune microbial responses, profileinterventions [28]. in Butyrate the prevention also or enhances amelioration extra-thymic of differentiation of Treg cells, while other SCFA, such as acetate, block this process [54]. Treg differentiationwith ofgeneration Treg cells,of auto-reactive while other T cells, SCFA, may suchtype 1 as diabetes. acetate, block this process [54]. Treg differentiationoccur seemsdue to tobacterial be related cell componentsto histone (auto-acetylation in the promoter of the Foxp3 locus, which is differentiation seems to be related to histone acetylation in the promoter of the Foxp3 locus, which also regulatedantigenic by butyratemimics) in [36].the microbiota. This suggests Mechanisms that microbiotaWhat is the‐derived relationship products between function the as mediators is also regulatedthat mediate by such butyrate immune [36 changes]. This may suggestsinclude microbiota that microbiota-derived and type 2 diabetes? products function as mediators inactivation the communication of Toll-like receptors between (proteins bacteria 7 andThe themicrobiota host immune may system,influence leading human to pro- or anti-inflammatorythat play responsesa key role [in54 ],immune and could systems) be aby factor metabolism involved through in β -cella number autoimmunity of mechanisms. and T1D. Systemicgut bacteria effects themselves of intestinal or through butyrate G protein- in theLipopolysaccharides regulatory immune (LPS) responsefrom the capsule also occur at the pancreaticcoupled level. receptor Butyrate(GPCR) stimulation has been by bacterial associated of gram-negative with the expression bacilli activate of inflammatory cathelicidin-related metabolites (Round et al, 2011). In addition, gut signalling pathways, via Toll-like receptor 4, antimicrobial peptide (CRAMP) in the β-cells of NOD mice. This peptide has been shown to protect bacteria-derived -associated molecular resulting in inflammation and diminishing insulin against thepatterns development (PAMPs) ofcan T1D induce by inducinginflammation a regulatory and sensitivity response (Cani andet al, suppressing2007). High-fat the diets inflammatory can process in thelead pancreaticto beta-cell isletsdestruction of prediabetic by inflammatory mice [ 55affect]. the microbiota and increase LPS levels Free fatty acid receptor 2 (FFAR2) is one of the G protein-coupled receptors that can be activated by microbiota-derivedG-protein coupled butyrate.receptors (GPCR) This=A large receptor family of is involvedimmune responses. in the insulin signaling regulation in molecules (from small to large) on the cell membrane Pathogen-associated molecular patterns adipose tissuethat andtrigger incellular the responses maintenance due to particular of energy .(PAMPs)=Molecules Its activation associated with promotes pathogens that the secretion of GLP-1 in themolecules intestine, outside the the cell. suppression of fat accumulation,are recognised and, by cells therefore, of the innate increased immune system, sensitivity to insulin [56].Lipopolysaccharides This is an interesting (LPS)=Large molecules mechanism consisting because of which even triggers though inflammation. the main problem in T1D is not a lipid and a polysaccharide that are found in the outer Toll-like receptor 4=A receptor responsible for activating insulin resistance,membrane the of Gram-negative diabetes accelerator bacteria, and elicit theory strong putsthe it ininnate context. immune response. This theory proposes that in T1D, body constitution, insulin resistance, and autoimmunity are three processes that accelerate the loss of 170 beta-cells by apoptosis [57]. This theory arises when observingDiabetes that children& Primary Care with Vol autoimmunity18 No 4 2016 that progress more quickly to T1D have greater insulin resistance than those non-progressors [58]. Thus, decreased production of butyrate in children with low levels of Prevotella in their gut microbiota could be contributing to T1D development. Kostic et al. [45], in the DIABIMMUNE study, followed children with high genetic risk for T1D from the first days following birth. Their results show associations between the gut bacterial communities and metabolic profile in young children, such as the levels of Blautia with long-chain triglycerides and Ruminococcus with short-chain triglycerides. Furthermore, these two

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either through increased epithelial permeability Box 1. The influence of microbes on metabolism (Allin et al, 2015). or enhanced uptake in chlyomicrons from the intestinal epithelium itself (Hildebrandt et al, A. Increased lipopolysaccharides increasing inflammation: A high-fat diet 2009; Box 1A). increases lipopolysaccharides (due to increased epithelial permeability There are also gut microbial mechanisms that or increased uptake of chylomicrons from the intestinal epithelium). counter this adverse metabolic effect and reduce Lipopolysaccharide from the capsule of gram-negative bacteria, interact and inflammation and increase insulin sensitivity. bind with Toll-like receptor 4 (TLR4), which increases inflammation and in Short-chain fatty acids (e.g. butyrate, acetate and turn reduces insulin sensitivity. propionate) arising from bacterial fermentation B. Bacteria in the colon ferment dietary fibres to short-chain fatty acids: of insoluble dietary fibre in the bowel can Short-chain fatty acids (e.g. butyrate, acetate, propionate) bind to G-coupled bind to GPR41 and GPR43 (Brahe et al, receptor protein and increase glucagon-like peptide (GLP)-1 and peptide YY, 2013). In immune cells, this results in reduced which decrease inflammation and increase insulin sensitivity. inflammation while in the L-cells, along the C. Increased secondary bile acids: Gut bacteria are capable of deconjugating digestive tract, it leads to increased glucagon-like primary bile acids, hindering their recirculation to the liver from the gut, and peptide (GLP)-1 and peptide YY (PYY) secretion further metabolising them to secondary bile acids. Secondary bile acids bind to the G protein-coupled receptor TGR5, which results in increased energy and improved insulin sensitivity (Tolhurst et al, expenditure in muscles and GLP1 secretion, both of which lead to improved 2012). The short-chain fatty acid butyrate exerts insulin sensitivity. key effects as an energy substrate in mucosal cells lining the colon, whereas acetate and propionate enhance hepatic gluconeogenesis and lipogenesis likelihood of developing type 2 diabetes (Allin (Box 1B). et al, 2015). In addition, bacteria can metabolise What has yet to be answered in humans is de-conjugated bile acids to secondary bile acids whether the gut microbiota is a cause – or result (Thomas et al, 2009). Secondary bile acids bind – of type 2 diabetes. Only prospective studies to the GPCR TGR5, which, in turn, increases will determine an association, and randomised GLP-1 production from L-cells and increases controlled treatment trials comparing placebo to energy expenditure in muscles leading to further health-promoting bacteria causality are ongoing. improvements in insulin sensitivity (Box 1C). Current evidence linking the microbiota to What is the relationship between the type 2 diabetes suggests that changes in the gut microbiota and obesity? microbiota (termed dysbiosis) can lead to epithelial There is increasing evidence linking the changes dysfunction and leakage. The increased intestinal in the bacterial composition of the microbiota epithelial permeability results in absorption of to obesity. Gut microbiota, for instance, that are large molecules from the bowel and, subsequently, transplanted from wild mice into germ-free mice to low-grade inflammation, immune dysfunction result in an increase in adiposity of the germ-free and alterations in glucose and lipid metabolism mice without increased food intake (Backhed et via signalling changes. These changes combine al, 2004). Obese mice have decreased Bacteroidetes to increase insulin resistance and enhance the and increased Firmicutes compared to lean mice

Chylomicrons=Small particles that transport dietary lipids Peptide YY=A small peptide released by cells in the from the intestines to other parts of the body, such as small intestines and colon in response to food. It acts to muscles and the liver. They are made of lipoprotein reduce appetite. particles. Primary bile acids=Bile acids synthesised by the liver. Deconjugation=The disruption of conjugated bacterial Short-chain fatty acids=Produced by bacteria in the gut cells, thus making them unstable. during fermentation of insoluble fibre from dietary plant Dysbosis=A microbial imbalance or maladaptation on or matter (e.g. acetate, propionate and butyrate). inside the body. TGR5=A cell surface receptor for bile acids, the receptor L-cells=Cells found mainly in the small and large is implicated in the suppression of intestines that secrete glucagon-like peptide (GLP)-1, functions and regulation of energy homeostasis by peptide YY, oxyntomodulin and GLP-2. bile acids.

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Page points (Ley et al, 2005). Moreover this tendency to Use of antibiotics in the early years of life has been 1. The correlation between the increase weight can be transferred to germ-free shown to disturb a healthy microbiota, with adverse microbiota and weight loss has mice by transplantation of the microbiota of the metabolic consequences, while other studies report been demonstrated; however, genetically obese mice. The transplanted mice then that antibiotics move a disturbed microbiota to a the correlation between the microbiota and weight gain ingest more energy from their diet and lose less in healthier state (i.e. in an opposite direction). It is is still to be conclusively excretions (Turnbaugh et al, 2006). argued, however, that the microbiota of the very determined. In obese humans, gene-encoded enzymes that early infant is particularly susceptible to microbial 2. The effect of antibiotics on the enhance breakdown of indigestible polysaccharides perturbation after antibiotic therapy (Ley et al, gut microbiota is still unknown, with past studies suggesting in the diet have been found in the microbiome, 2006). positive and negative effects. thus enabling greater energy extraction from 3. Improving the understanding a given food intake. It is also recognised that How might what we know about the of the association between intestinal permeability to LPS and change in bile microbiota influence future clinical the microbiota and the practice? development of type 1 diabetes, acid signalling accompany greater energy efficiency type 2 diabetes and obesity seen in studies of obese participants (Musso et Improved understanding of the association will allow the development of al, 2010). In addition, the use of the between the microbiota and the development of useful methods for prevention Lactobacillin reuteri in a small randomised type 1 diabetes, type 2 diabetes and obesity points or amelioration of these disease states. controlled trial of lean and obese humans without to potential useful methods for prevention or diabetes revealed an increase in plasma GLP-1 amelioration of these disease states. and GLP-2 – albeit with no change in glucose Current evidence suggests that adverse changes in tolerance. The significance of this is uncertain. the microbiota increase the risk of developing type 1 Whether this effect is mediated via bacterial diabetes through reduced bacterial diversity, leaky stimulation of the L-cells (either through direct gut barriers and increased inflammation. Various contact or through bacterially secreted substances) interventions including early administration of also remains unclear (Ferrannini, 2015). antibiotics that target Gram-negative bacteria, An experiment where mice were transplanted dietary modification including the use of pre- with the bowel contents from human twins biotics, administration of genetically altered discordant for obesity demonstrated that the Lactococcus lactis, use of bacterial metabolites obesity phenotype was transmissible. Interestingly, such as acetate, butyrate and propionate, and when obese and lean mice were placed together transplantation of microbiota have been shown to (mice are coprophagic*), no additional weight gain modulate the development of type 1 diabetes in was seen when the mice were fed a healthy mouse animal models. It remains to be seen how effective chow diet, but weight gain was recorded when they such strategies can be in human beings. were fed human cafeteria food. This underlines the In respect of type 2 diabetes and obesity, tendency of the microbiota to adjust according to there also remains much uncertainty of the the changing milieu of the intestinal tract (Ridaura value of chosen interventions. Transplantation et al, 2013). of donor microbiota into the intestine of people In addition, the correlation between the with recurrent Clostridium difficile infection is a microbiota and weight loss has been demonstrated. successful and established therapy (van Nood, Modulation of the microbiota by either fat or 2013). Using the same technique, improvements restriction results in an increase in in insulin sensitivity have been recorded when the Bacteroidetes as weight loss progresses. This offers microbiota of insulin-sensitive people, with low potential therapeutic options for both overweight BMIs, are transplanted into obese individuals with and underweight people. metabolic syndrome. How useful this pioneering technique may prove to be in the future remains to What effect do antibiotics play? be demonstrated and is not without its conceptual The relationship between antibiotic therapy and challenge for those receiving donor transplants the gut microbiota has attracted much interest. (Vrieze et al, 2012). The value of Lactobacilli supplementation as a treatment modality for *Eat their own faeces. dysbiosis (based on the premise that they are the

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first to colonise the sterile neonatal intestinal tracts microbial consortia in the developing infant gut microbiome. “Further research Proc Natl Acad Sci U S A 108(Suppl 1): 4578–85 during vaginal delivery and initial breast feeding) Kuczynski J, Lauber CL, Walters WA et al (2012) Experimental and into the microbiota has not been confirmed in systematic reviews and analytical tools for studying the human microbiome. Nat Rev Genet 13: 47–58 may provide, in meta-analyses to date (Ruan et al, 2015). Lederberg J, McCray AT (2001) ’Ome sweet ’ – a genealogical time, important treasury of words. The Scientist 15: 8 So where does this leave us? Ley RE, Backhed F, Turnbaugh P et al (2005) Obesity alters gut new strategies in . Proc Natl Acad Sci U S A 102: 11070 –5 Much has been learned about diabetes and obesity the management, through better understanding of the influence of Ley RE, Peterson DA, Gordon JI (2006) Ecological and evolutionary forces shaping microbioal diversity in the human intestine. Cell amelioration and the gut microbiota on metabolism in humans. 124: 837–48 While treatment methods based on present Li J, Jia H, Cai X et al (2014) An integrated catalog of reference genes possible prevention of in the human gut microbiome. Nat Biotechnol 32: 834–41 diabetes and obesity.” understanding of the interaction between nutrition Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An and the microbiota have yet to prove of significant immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122: 107–18 benefit to those with diabetes or obesity, it is likely Mejía-León ME, Calderón de la Barca AM (2015) Diet, microbiota that interest in interventions based on reversal of and immune system in type 1 diabetes development and these changes will continue. . Nutrients 7: 9171– 84 Musso G, Gambino R, Cassader M (2010) Obesity, diabetes, and gut We all recognise the link between food and microbiota: The hygiene hypothesis expanded. Diabetes Care 33: our health. The unfolding role of the microbiota 2277–84 and its effect on our metabolism makes intrinsic Power SE, O’Toole PW, Stanton C et al (2014) Intestinal microbiota, diet and health. Br J Nutr 111: 387–402 sense. Further research into the microbiota may Qin J, Li R, Raes J et al (2010) A human gut microbial gene catalogue provide, in time, important new strategies in the established by metagenomic sequencing. Nature 464: 59–65 management, amelioration and possible prevention Ridaura VK, Faith JJ, Rey FE et al (2013) Gut microbiota from twins discordant for obesity modulate adiposity and metabolic of diabetes and obesity. n phenotypes in mice. Science 341: 1241214 Round JL, Lee SM, Li J et al (2011) The Toll-like receptor 2 pathway Allin KH, Nielsen T, Pedersen O (2015) Gut microbiota in patients establishes colonization by a commensal of the human with type 2 diabetes mellitus. Eur Endocrinol 172: R167–R177 microbiota. Science 332: 974–7 Arumugam M, Raes J, Pelletier E et al (2011) Enterotypes of the human gut microbiome. Nature 473: 174– 80 Ruan Y, Sun J, He J et al (2015) Effect of on glycemic control: a systematic review and meta-analysis of randomized, Backhed F, Ding H, Wang T et al (2004) The gut microbiota as an controlled trials. PLoS One 10: e0132121 environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101:15718–23 Suzuki T, Takao YT, Fujimura T et al (1987) Diabetogenic effects of lymphocyte transfusion on the NOD or NOD nude mice. Brahe LK, Astrup A, Larsen LH (2013) Is butyrate the link between In: Rygaard MB, Graem N, Sprang-Thomsen M (eds). Immune- diet, intestinal microbiota and obesity-related metabolic diseases? deficient animals in biomedical research. Karger, Basel, Obes Rev 14: 950–9 Switzerland: 112–6 Cani PD, Amar J, Iglesias MA et al (2007) Metabolic endotoxemia Thomas C, Gioiello A, Noriega L et al (2009) TGR5-mediated bile initiates obesity and insulin resistance. Diabetes 56: 1761–72 acid sensing controls glucose homeostasis. Cell Metab 10: 167–7 de Goffau MC, Luopajarvi K, Knip M et al (2013) Fecal microbiota Tolhurst G, Heffron H, Lam YS et al (2012) Short-chain fatty acids composition differs between children with beta-cell stimulate glucagon-like peptide-1 secretion via the G-protein- autoimmunity and those without. Diabetes 62: 1238–44 coupled receptor FFAR2. Diabetes 61: 364–71 de Goffau MC, Fuentes S, van den Bogert B et al (2014) Aberrant gut microbiota composition at the onset of type 1 diabetes in young Turnbaugh PJ, Ley RE, Mahowald MA et al (2006) An obesity- children. Diabetologia 57: 1569–77 associated gut microbiome with increased capacity for energy harvest. Nature 444: 1027–31 Dobell C (1920) The discovery of intestinal in man. Proc R Soc Med 13: 1–15 Turnbaugh PJ, Hamady M, Yatsunenko T et al (2009) A core gut microbiome in obese and lean twins. Nature 457: 480–4 Dominguez-Bello MG, Costello EK, Contreras M et al (2010) Delivery mode shapes the acquisition and structure of the initial Ursell LK, Metcalf JL, Parfrey LW, Knight R (2012) Defining the microbiota across multiple body habitats in newborns. Proc Natl human microbiome. Nutr Rev 70(Suppl 1): S38–S44 Acad Sci U S A 107: 11971–5 van Leeuwenhoek A (1684) An abstract of a letter from Antonie van Dominguez-Bello MG, Blaser MJ, Ley RE et al (2011) Development Leeuwenhoek, dated Sept. 12, 1683, about animals in the scurf of of the human gastrointestinal microbiota and insights from high- the teeth. Philos Trans R Soc Lond 14: 568 –74 throughput sequencing. Gastroenterology 140: 1713–9 van Nood E, Vrieze A, Nieuwdorp M et al (2013) Duodenal infusion Ferrannini E (2015) Of microbes and men. Diabetes Care 38: 1817–9 of donor feces for recurrent Clostridium difficile. N Engl J Med Giongo A, Gano KA, Crabb DB et al (2011) Toward defining the 368: 407–15 autoimmune microbiome for type 1 diabetes. ISME J 582–91 Vrieze A, Van Nood E, Holleman F et al (2012) Transfer of intestinal Hague A, Butt AJ, Paraskeva C (1996) The role of butyrate in microbiota from lean donors increases insulin sensitivity in human colonic epithelialcells: an energy source or inducer of individuals with metabolic syndrome. Gastroenterology 143: differentiation and apoptosis? Proc Nutr Soc 55: 937–43 913–6 Hildebrandt MA, Hoffmann C, Sherrill-Mix SA et al (2009) High-fat Weinstock GM (2012) Genomic approaches to studying the human diet determines the composition of the murine gut microbiome microbiota. Nature 489: 250–6 independently of obesity. Gastroenterology 137: 1716 –24 Wu GD, Chen J, Hoffmann C et al (2011) Linking long-term dietary Koenig JE, Spor A, Scalfone N et al (2011) Succession of patterns with gut microbial enterotypes. Science 334: 105–8

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