Obesity and the Microbiota
2009; Elsevier BV; Volume: 136; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2009.03.030
ISSN1528-0012
AutoresHerbert Tilg, Alexander R. Moschen, Arthur Kaser,
Tópico(s)Dietary Effects on Health
ResumoSee related content in the May supplemental issue of Gastroenterology.The enormous number and diversity of microorganisms in the human intestine contribute a diverse set of functions, which complement the host for important features such as digestion of complex carbohydrates. Conventionalization of germ-free mice with a normal gut microbiota harvested from the distal intestine of conventionally raised mice leads to weight gain, obesity, and insulin resistance, suggesting that the gut microbiota may affect energy absorption. In addition, development of obesity in genetically or diet-induced obese mice is associated with substantial changes in the composition and metabolic function of the gut microbiota. This trait is even transmissible as colonization of germ-free mice with an “obese gut microbiota” results in a greater increase in total body fat than colonization with a “lean gut microbiota.” Recent studies in obese and lean twins suggest that an extensive core gut microbiome (ie, collective genome of the gut microbiota) exists, and that obese individuals exhibit reduced diversity and an altered representation of metabolic pathways in their microbiota. Moreover, the gut microbiota and its products directly regulate host gene expression and thereby control host energy expenditure and storage. Although human data are still in beginning stages, current findings support a concept that the gut microbiome together with host genotype and life style might contribute to the development of obesity.IntroductionThe incidence of obesity and its associated disorders has increased dramatically worldwide. Obesity predisposes individuals to an increased risk of developing several diseases, including atherosclerosis, diabetes, nonalcoholic fatty liver disease, certain cancers, and some immune-mediated disorders. In addition to these associations with disease, research in the past few years has identified important pathways that link metabolism with the immune system and vice versa. The development of obesity is a complex process involving genetic and environmental factors. Several genes have been implicated in the determination of body weight, which are predicted to affect control of appetite, energy expenditure, and further metabolic functions.1Frayling T.M. Timpson N.J. Weedon M.N. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3290) Google Scholar, 2Loos R.J. Lindgren C.M. Li S. et al.Common variants near MC4R are associated with fat mass, weight and risk of obesity.Nat Genet. 2008; 40: 768-775Crossref PubMed Scopus (1017) Google Scholar, 3Chambers J.C. Elliott P. Zabaneh D. et al.Common genetic variation near MC4R is associated with waist circumference and insulin resistance.Nat Genet. 2008; 40: 716-718Crossref PubMed Scopus (398) Google Scholar, 4Thorleifsson G. Walters G.B. Gudbjartsson D.F. et al.Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.Nat Genet. 2009; 41: 18-24Crossref PubMed Scopus (1047) Google Scholar, 5Sabatti C. Service S.K. Hartikainen A.L. et al.Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.Nat Genet. 2009; 41: 35-46Crossref PubMed Scopus (568) Google Scholar, 6Willer C.J. Speliotes E.K. Loos R.J. et al.Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.Nat Genet. 2009; 41: 25-34Crossref PubMed Scopus (1361) Google Scholar, 7Meyre D. Delplanque J. Chevre J.C. et al.Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.Nat Genet. 2009; 41: 157-159Crossref PubMed Scopus (514) Google Scholar, 8Cecil J.E. Tavendale R. Watt P. et al.An obesity-associated FTO gene variant and increased energy intake in children.N Engl J Med. 2008; 359: 2558-2566Crossref PubMed Scopus (523) Google Scholar However, this genetic susceptibility might only explain a small fraction of overall susceptibility to obesity, and moreover certainly cannot explain the rise in incidence of this disease, which is apparently associated with our Western diet. Overall, the complex pathways that lead to development of obesity and its consequences are poorly understood.The human gut contains an enormous number and diversity of microorganisms referred to as the gut microbiota.9Turnbaugh P.J. Ley R.E. Hamady M. et al.The human microbiome project.Nature. 2007; 449: 804-810Crossref PubMed Scopus (3485) Google Scholar, 10Hooper L.V. Gordon J.I. Commensal host-bacterial relationships in the gut.Science. 2001; 292: 1115-1118Crossref PubMed Scopus (1751) Google Scholar, 11Ley R.E. Peterson D.A. Gordon J.I. Ecological and evolutionary forces shaping microbial diversity in the human intestine.Cell. 2006; 124: 837-848Abstract Full Text Full Text PDF PubMed Scopus (2232) Google Scholar The human gut microbiota consists of at least 1014 bacteria, including up to 2000 species dominated by anaerobic bacteria.12Neish A.S. Microbes in Gastrointestinal Health and Disease.Gastroenterology. 2009; 136: 65-80Abstract Full Text Full Text PDF PubMed Scopus (938) Google Scholar Beside major interactions with our innate immune system, the collective genome of our gut microbiota (gut microbiome) encodes for many metabolic functions which are unique and cannot be performed by ourselves. Although many metabolic functions are unexplored, they include, for example, the processing of otherwise indigestible components of our diet such as plant polysaccharides.Recent landmark studies, preeminently originating from Dr Jeffrey I. Gordon's laboratory at Washington University, have investigated the relationship of the intestinal microbial flora with obesity. These studies revealed that obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota that allows the “obese microbiota” to extract more energy from the diet. Moreover, these studies have also shown that the gut microbiota and its products interact with host pathways and “sensors” and thereby direct energy expenditure and storage at the host side. This article provides a brief overview of this exciting, emerging field.The Gut Microbiota Affects Host Genes That Regulate Energy Expenditure and StorageThe first striking and unequivocal evidence on a role of the gut microbiota on host adiposity came from studies in germ-free mice. Conventionally raised mice contained 42% more total body fat compared to those raised under germ-free conditions.13Backhed F. Ding H. Wang T. et al.The gut microbiota as an environmental factor that regulates fat storage.Proc Natl Acad Sci U S A. 2004; 101: 15718-15723Crossref PubMed Scopus (4187) Google Scholar Conventionalization of germ-free mice via colonization with a cecum-derived, distal microbial community produced a dramatic increase in total body fat content, which was not associated with differences in chow consumption or decreased energy expenditure.13Backhed F. Ding H. Wang T. et al.The gut microbiota as an environmental factor that regulates fat storage.Proc Natl Acad Sci U S A. 2004; 101: 15718-15723Crossref PubMed Scopus (4187) Google Scholar The gut microbiota directed increased monosaccharide uptake from the gut and instructed the host to increase hepatic production of triglycerides, which was associated with the development of insulin resistance. It had earlier been shown that colonization of germ-free mice substantially alters the transcriptional profile in the intestine, in particular epithelial cells, hence regulating important intestinal functions like nutrient absorption, mucosal barrier fortification, xenobiotic metabolism, angiogenesis, and postnatal intestinal maturation.14Hooper L.V. Wong M.H. Thelin A. et al.Molecular analysis of commensal host-microbial relationships in the intestine.Science. 2001; 291: 881-884Crossref PubMed Scopus (1666) Google Scholar Conventionalization indeed suppressed intestinal expression of fasting-induced adipose factor (Fiaf) specifically in differentiated villous epithelial cells in the ileum.13Backhed F. Ding H. Wang T. et al.The gut microbiota as an environmental factor that regulates fat storage.Proc Natl Acad Sci U S A. 2004; 101: 15718-15723Crossref PubMed Scopus (4187) Google Scholar Fiaf (also known as angiopoietin-like protein 4) is a circulating lipoprotein lipase (LPL) inhibitor produced not only by the intestine, but also by liver and adipose tissue.15Yoon J.C. Chickering T.W. Rosen E.D. et al.Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation.Mol Cell Biol. 2000; 20: 5343-5349Crossref PubMed Scopus (337) Google Scholar Increased adipocyte LPL activity leads to increased cellular uptake of fatty acids and adipocyte triglyceride accumulation. Indeed, germ-free Fiaf−/− mice have the same amount of total body fat weight as conventionalized (Fiaf-suppressed) mice, establishing Fiaf as a prominent mediator of microbial regulation of peripheral fat storage.13Backhed F. Ding H. Wang T. et al.The gut microbiota as an environmental factor that regulates fat storage.Proc Natl Acad Sci U S A. 2004; 101: 15718-15723Crossref PubMed Scopus (4187) Google ScholarA second pathway apart from Fiaf involves adenosine monophosphate (AMP)-activated protein kinase (AMPK) that protects mice from obesity produced by consumption of a high-fat, high-sugar, Western diet.16Backhed F. Manchester J.K. Semenkovich C.F. et al.Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.Proc Natl Acad Sci U S A. 2007; 104: 979-984Crossref PubMed Scopus (1867) Google Scholar AMPK is an enzyme that is conserved from yeast to humans and functions as a “fuel gauge” that monitors cellular energy status; it is activated in response to metabolic stresses that result in an increased intracellular ratio of AMP to adenosine triphosphate.17Kahn B.B. Alquier T. Carling D. et al.AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism.Cell Metab. 2005; 1: 15-25Abstract Full Text Full Text PDF PubMed Scopus (2294) Google Scholar Germ-free mice persistently remained lean despite high calorie intake.16Backhed F. Manchester J.K. Semenkovich C.F. et al.Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.Proc Natl Acad Sci U S A. 2007; 104: 979-984Crossref PubMed Scopus (1867) Google Scholar This state was associated consistently with increased activity of phosphorylated AMPK levels both in liver and skeletal muscle, which stimulated fatty acid oxidation in peripheral tissues and led to decreased glycogen levels, along with increased insulin sensitivity, in the liver.16Backhed F. Manchester J.K. Semenkovich C.F. et al.Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.Proc Natl Acad Sci U S A. 2007; 104: 979-984Crossref PubMed Scopus (1867) Google Scholar These data suggest that the presence of a gut microbiota suppresses skeletal muscle fatty acid oxidation through a metabolic pathway that may involve phosphorylation of AMPK.16Backhed F. Manchester J.K. Semenkovich C.F. et al.Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.Proc Natl Acad Sci U S A. 2007; 104: 979-984Crossref PubMed Scopus (1867) Google ScholarThe 3rd pathway that affects host energy storage again involves intestinal epithelial cells as sensors of microbial products. The host proteome has a very limited repertoire of glycoside hydrolases needed to digest complex dietary plant polysaccharides: the gut microbiota synthesizes a large arsenal of these enzymes18Backhed F. Ley R.E. Sonnenburg J.L. et al.Host-bacterial mutualism in the human intestine.Science. 2005; 307: 1915-1920Crossref PubMed Scopus (3536) Google Scholar, 19Flint H.J. Bayer E.A. Rincon M.T. et al.Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis.Nat Rev Microbiol. 2008; 6: 121-131Crossref PubMed Scopus (1121) Google Scholar and allows us to process complex dietary carbohydrates to monosaccharides and short-chain fatty acids (SCFAs), principally acetate, propionate, and butyrate. These SCFAs as end-products of bacterial fermentation therefore represent a common and important energy source for our body. SCFAs not only diffuse passively or are recovered via monocarboxylic acid transporters, but may also act as signaling molecules. Proprionate and acetate are ligands for 2 G-protein–coupled receptors (GPCRs): Gpr41 and Gpr43.20Brown A.J. Goldsworthy S.M. Barnes A.A. et al.The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids.J Biol Chem. 2003; 278: 11312-11319Crossref PubMed Scopus (1518) Google Scholar, 21Le Poul E. Loison C. Struyf S. et al.Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation.J Biol Chem. 2003; 278: 25481-25489Crossref PubMed Scopus (1061) Google Scholar These GPCRs are mainly expressed by gut epithelial cells, in particular enteroendocrine cells. Conventionally raised Gpr41−/− mice or germ-free Gpr41−/− mice colonized with Bacteroidetes theatiotaomicron (saccharolytic) and Methanobrevibacter smithii (methanogenic) were significantly leaner than wild-type littermates, whereas there were no genotype-related differences in germ-free mice.22Samuel B.S. Shaito A. Motoike T. et al.Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.Proc Natl Acad Sci U S A. 2008; 105: 16767-16772Crossref PubMed Scopus (1103) Google Scholar Gpr41 deficiency was associated with decreased expression of peptide YY, an enteroendocrine cell-derived hormone that normally inhibits gut motility, faster intestinal transit rate, and reduced harvest of energy (SCFAs) from the diet.22Samuel B.S. Shaito A. Motoike T. et al.Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.Proc Natl Acad Sci U S A. 2008; 105: 16767-16772Crossref PubMed Scopus (1103) Google Scholar These experiments hence revealed that Gpr41 might be a regulator of host energy balance through effects that are dependent on the gut microbiota and their metabolic capacity.22Samuel B.S. Shaito A. Motoike T. et al.Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.Proc Natl Acad Sci U S A. 2008; 105: 16767-16772Crossref PubMed Scopus (1103) Google Scholar Moreover, the capacity to ferment carbohydrates to SCFA varies greatly among bacterial species, so that the actual composition of the intestinal microbial flora in a given individual may be an individual contributor to host energy metabolism. This latter aspect leads to a later discussion, namely the role of the gut microbiota in the energy harvest from the diet.Altogether, these 3 pathways (Fiaf, AMPK, and Gpr41) highlight how the gut microbiota and its products directly regulate host gene expression and thereby affect host energy expenditure and storage. It is noteworthy that 2 of these pathways involve the intestinal epithelium as “sensor” of the gut microbiota, hence implicating a major role for the intestinal epithelium in determining leanness and obesity (Figure 1).The Gut Microbiota Affects Energy Harvest From the Diet: Differences in Microbial Composition Between Lean and Obese Mice/HumansThe gut microbiota benefits the host in numerous ways, among them contributing the capability to extract calories from otherwise indigestible common polysaccharides in our diet.19Flint H.J. Bayer E.A. Rincon M.T. et al.Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis.Nat Rev Microbiol. 2008; 6: 121-131Crossref PubMed Scopus (1121) Google Scholar Components of the gut microbiota are able to adaptively deploy a large array of glycoside hydrolases and polysaccharide lyases that humans do not encode in their genome.23Sonnenburg J.L. Xu J. Leip D.D. et al.Glycan foraging in vivo by an intestine-adapted bacterial symbiont.Science. 2005; 307: 1955-1959Crossref PubMed Scopus (806) Google Scholar, 24Xu J. Bjursell M.K. Himrod J. et al.A genomic view of the human-Bacteroides thetaiotaomicron symbiosis.Science. 2003; 299: 2074-2076Crossref PubMed Scopus (1006) Google Scholar Ley et al25Ley R.E. Backhed F. Turnbaugh P. et al.Obesity alters gut microbial ecology.Proc Natl Acad Sci U S A. 2005; 102: 11070-11075Crossref PubMed Scopus (4210) Google Scholar tested the hypothesis that differences in gut microbial ecology between individuals may be an important factor affecting energy homeostasis. Analysis of 16S rRNA sequences of the distal gut microbiota of genetically obese ob/ob mice, lean ob/+ and wild-type siblings, and their ob/+ mothers, all fed the same polysaccharide-rich diet, revealed that ob/ob mice have a 50% reduction in the abundance of Bacteriodetes and a proportional increase in Firmicutes.25Ley R.E. Backhed F. Turnbaugh P. et al.Obesity alters gut microbial ecology.Proc Natl Acad Sci U S A. 2005; 102: 11070-11075Crossref PubMed Scopus (4210) Google Scholar Ob/ob mice also harbored more methanogenic Archaea, which may increase efficiency of bacterial fermentation via removal of H2.26Turnbaugh P.J. Ley R.E. Mahowald M.A. et al.An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (7897) Google Scholar Studies with the principal methanogenic archaeon in the human gut, M smithii, along with B thetaiotaomicron, showed that co-colonization not only enhanced efficiency, but also changed the specificity of bacterial polysaccharide fermentation, increasing adiposity compared with mice colonized with either organism alone.27Samuel B.S. Gordon J.I. A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism.Proc Natl Acad Sci U S A. 2006; 103: 10011-10016Crossref PubMed Scopus (469) Google ScholarThese differences in microbial composition were divisionwide, and not attributable to differences in food consumption (a runted ob/ob mouse weighed less than his ob/ob littermates owing to reduced chow consumption, but still exhibited a markedly higher percent body fat and ratio of Firmicutes to Bacteroidetes),25Ley R.E. Backhed F. Turnbaugh P. et al.Obesity alters gut microbial ecology.Proc Natl Acad Sci U S A. 2005; 102: 11070-11075Crossref PubMed Scopus (4210) Google Scholar albeit this latter aspect requires further study in light of results from diet-induced obesity experiments, as discussed below.28Turnbaugh P.J. Backhed F. Fulton L. et al.Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.Cell Host Microbe. 2008; 3: 213-223Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar Analogous differences in the distal gut microbiota were observed in initial studies in lean versus obese humans29Ley R.E. Turnbaugh P.J. Klein S. et al.Microbial ecology: human gut microbes associated with obesity.Nature. 2006; 444: 1022-1023Crossref PubMed Scopus (5945) Google Scholar (Figure 2). It had earlier been suggested that ob/ob mice are more efficient at harvesting energy from food than are lean wild-type animals.30Ferraris R.P. Vinnakota R.R. Intestinal nutrient transport in genetically obese mice.Am J Clin Nutr. 1995; 62: 540-546PubMed Google Scholar, 31Warwick B.P. Romsos D.R. Energy balance in adrenalectomized ob/ob mice: effects of dietary starch and glucose.Am J Physiol. 1988; 255: R141-R148PubMed Google Scholar In the first metagenomic analysis of the distal intestinal flora, Turnbaugh et al26Turnbaugh P.J. Ley R.E. Mahowald M.A. et al.An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (7897) Google Scholar performed random shotgun sequencing of the cecal microbiota of ob/ob, ob/+, and +/+ littermates.26Turnbaugh P.J. Ley R.E. Mahowald M.A. et al.An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (7897) Google Scholar Through these metagenomic and biochemical analysis, they demonstrated that the changes in the relative abundance of Bacteroidetes and Firmicutes was associated with the metabolic potential of the microbiota.26Turnbaugh P.J. Ley R.E. Mahowald M.A. et al.An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (7897) Google Scholar The obese gut microbiome had an increased capacity to harvest energy from the diet. Moreover, this trait was transmissible in that colonization of germ-free mice with an “obese gut microbiota” resulted in a significantly greater increase in total body fat compared with colonization with a “lean gut microbiota.”26Turnbaugh P.J. Ley R.E. Mahowald M.A. et al.An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (7897) Google Scholar With regard to increased energy harvest from the diet, a recent study by Zhang et al32Zhang H. DiBaise J.K. Zuccolo A. et al.Human gut microbiota in obesity and after gastric bypass.Proc Natl Acad Sci U S A. 2009; 106: 2365-2370Crossref PubMed Scopus (1337) Google Scholar on 16S rRNA sequencing of stool from a limited number of lean and obese participants and patients after gastric bypass surgery for weight reduction, revealed that H2-producing Prevotellaceae and certain groups within Firmicutes were enriched in obese individuals, along with higher numbers of H2-utilizing methanogenic Archaea.32Zhang H. DiBaise J.K. Zuccolo A. et al.Human gut microbiota in obesity and after gastric bypass.Proc Natl Acad Sci U S A. 2009; 106: 2365-2370Crossref PubMed Scopus (1337) Google Scholar Such coexistence of H2-producing Bacteria with relatively high numbers of H2-utilizing methanogenic Archaea in the gastrointestinal tract of obese individuals led to the hypothesis that interspecies H2 transfer between bacterial and archaeal species might indeed be an important mechanism for increasing energy uptake by the human large intestine in obese persons,32Zhang H. DiBaise J.K. Zuccolo A. et al.Human gut microbiota in obesity and after gastric bypass.Proc Natl Acad Sci U S A. 2009; 106: 2365-2370Crossref PubMed Scopus (1337) Google Scholar as had been suggested from murine studies, as discussed.26Turnbaugh P.J. Ley R.E. Mahowald M.A. et al.An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (7897) Google Scholar, 27Samuel B.S. Gordon J.I. A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism.Proc Natl Acad Sci U S A. 2006; 103: 10011-10016Crossref PubMed Scopus (469) Google Scholar The accelerated fermentation by the human obese microbiota may stimulate the hydrolysis of usually indigestible organic matter and may lead to increased production of SCFA, especially acetate, which are absorbed by the human gut and might perform important regulatory functions on the host side as well.22Samuel B.S. Shaito A. Motoike T. et al.Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.Proc Natl Acad Sci U S A. 2008; 105: 16767-16772Crossref PubMed Scopus (1103) Google Scholar, 32Zhang H. DiBaise J.K. Zuccolo A. et al.Human gut microbiota in obesity and after gastric bypass.Proc Natl Acad Sci U S A. 2009; 106: 2365-2370Crossref PubMed Scopus (1337) Google ScholarFigure 2Genetic and diet-induced obesity are associated with alterations of (i) the composition and (ii) the functional properties of the gut microbiota. (A) Leptin-deficient ob/ob mice rapidly gain weight. Development of obesity correlates with a shift in the abundance of the 2 dominating divisions, the Bacteroidetes and the Firmicutes. Compared to lean ob/+ or +/+ littermates, obesity was associated with a 50% reduction in Bacteroidetes and a proportional division-wide increase in Firmicutes. Moreover, ob/ob mice showed an increase in environmental gene tags that matched Archaea, methanogenic microorganisms that might promote bacterial fermentation by removing one of its end products, namely hydrogen (H2). The metagenomic analysis of the obese gut microbiome revealed an increase in glycoside hydrolases, capable of breaking down otherwise indigestible alimentary polysaccharides. Furthermore, the obese microbiome showed enrichment for transport proteins and fermentation enzymes further processing breakdown products. As a consequence, ob/ob mice have an increased capacity to harvest energy from their diet. (B) The interrelationship between diet, intestinal microbial ecology, and energy homeostasis was investigated in a mouse model of diet-induced obesity.28Turnbaugh P.J. Backhed F. Fulton L. et al.Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.Cell Host Microbe. 2008; 3: 213-223Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar The microbiota of mice fed a high-fat/high-sugar prototypic Western diet was compared with the microbiota of mice receiving a low-fat/high-polysaccharide diet. Again, as in the ob/ob model, the Western diet was associated with an increased body weight, a lower relative abundance of Bacteroidetes, and a higher relative abundance of Firmicutes. However, unlike in the ob/ob model this shift was not division-wide. The overall diversity of the Western diet-associated gut microbiota dropped dramatically. The reason was a bloom in a single class of the Firmicutes—the Mollicutes. The Western diet gut microbiome was enriched for genes involved in import and fermentation of simple sugars and host glycans, enriched for genes for beta-fructosidases, and depleted for genes involved in motility.View Large Image Figure ViewerDownload Hi-res image Download (PPT)It is well known that ob/ob mice consume substantially more chow than their lean ob/+ or +/+ littermates.25Ley R.E. Backhed F. Turnbaugh P. et al.Obesity alters gut microbial ecology.Proc Natl Acad Sci U S A. 2005; 102: 11070-11075Crossref PubMed Scopus (4210) Google Scholar Moreover, the root cause of obesity is excess caloric intake compared with expenditure, a view that is also supported by genome-wide association studies that identified several genes in pathways that may be associated with a hyperphagic state.1Frayling T.M. Timpson N.J. Weedon M.N. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3290) Google Scholar, 2Loos R.J. Lindgren C.M. Li S. et al.Common variants near MC4R are associated with fat mass, weight and risk of obesity.Nat Genet. 2008; 40: 768-775Crossref PubMed Scopus (1017) Google Scholar, 3Chambers J.C. Elliott P. Zabaneh D. et al.Common genetic variation near MC4R is associated with waist circumference and insulin resistance.Nat Genet. 2008; 40: 716-718Crossref PubMed Scopus (398) Google Scholar, 4Thorleifsson G. Walters G.B. Gudbjartsson D.F. et al.Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.Nat Genet. 2009; 41: 18-24Crossref PubMed Scopus (1047) Google Scholar, 5Sabatti C. Service S.K. Hartikainen A.L. et al.Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.Nat Genet. 2009; 41: 35-46Crossref PubMed Scopus (568) Google Scholar, 6Willer C.J. Speliotes E.K. Loos R.J. et al.Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.Nat Genet. 2009; 41: 25-34Crossref PubMed Scopus (1361) Google Scholar, 7Meyre D. Delplanque J. Chevre J.C. et al.Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.Nat Genet. 2009; 41: 157-159Crossref PubMed Scopus (514) Google Scholar, 8Cecil J.E. Tavendale R. Watt P. et al.An obesity-associated FTO gene variant and increased energy intake in children.N Engl J Med. 2008; 359: 2558-2566Crossref PubMed Scopus (523) Google Scholar Host genotype may have dramatic effects on the composition and functional profile of the gut microbiota.33Garrett W.S. Lord G.M. Punit S. et al.Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system.Cell. 2007; 131: 33-45Abstract Full Text Full Text PDF PubMed Scopus (744) Google Scholar, 34Wen L. Ley R.E. Volchkov P.Y. et al.Innate immunity and intestinal microbiota in the development of Type 1 diabetes.Nature. 2008; Google Scholar An important question, therefore, is whether the alterations in the microbiota of ob/ob mice are a consequence of host genotype or the hyperphagic state.In a subsequent study, Turnbaugh et al28Turnbaugh P.J. Backhed F. Fulton L. et al.Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.Cell Host Microbe. 2008; 3: 213-223Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar developed a model of Western diet-induced obesity to investigate the interrelationship between diet, gut microbial ecology, and energy balance. Diet-induced obesity produced a bloom in a single uncultured clade within the Mollicutes class of the Firmicutes, which was diminished by subsequent dietary manipulations that limit weight gain
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