Responses of Gut Microbiota and Glucose and Lipid Metabolism to Prebiotics in Genetic Obese and Diet-Induced Leptin-Resistant Mice

OBJECTIVE To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice. RESEARCH DESIGN AND METHODS Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models. RESULTS In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat–fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters. CONCLUSIONS We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

[1]  R. Knight,et al.  The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice , 2009, Science Translational Medicine.

[2]  Rob Knight,et al.  UniFrac – An online tool for comparing microbial community diversity in a phylogenetic context , 2006, BMC Bioinformatics.

[3]  T. van de Wiele,et al.  Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability , 2009, Gut.

[4]  A. Goldfine,et al.  Inflammation and insulin resistance. , 2006, The Journal of clinical investigation.

[5]  R. Knight,et al.  Responses of Gut Microbiota to Diet Composition and Weight Loss in Lean and Obese Mice , 2012, Obesity.

[6]  W. D. de Vos,et al.  Comparative Analysis of Pyrosequencing and a Phylogenetic Microarray for Exploring Microbial Community Structures in the Human Distal Intestine , 2009, PloS one.

[7]  F. Bäckhed,et al.  The endocannabinoid system links gut microbiota to adipogenesis , 2010, Molecular systems biology.

[8]  P. François,et al.  Altered Gut Microbiota and Endocannabinoid System Tone in Obese and Diabetic Leptin-Resistant Mice: Impact on Apelin Regulation in Adipose Tissue , 2011, Front. Microbio..

[9]  P. Brun,et al.  Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[10]  R. Ley,et al.  Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5 , 2010, Science.

[11]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[12]  E. Zoetendal,et al.  Microarray Analysis and Barcoded Pyrosequencing Provide Consistent Microbial Profiles Depending on the Source of Human Intestinal Samples , 2011, Applied and Environmental Microbiology.

[13]  J. Ferrières,et al.  Metabolic Endotoxemia Initiates Obesity and Insulin Resistance , 2007, Diabetes.

[14]  R. Ley,et al.  Ecological and Evolutionary Forces Shaping Microbial Diversity in the Human Intestine , 2006, Cell.

[15]  Rob Knight,et al.  High-fat diet determines the composition of the murine gut microbiome independently of obesity. , 2009, Gastroenterology.

[16]  E. Murphy,et al.  Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models , 2010, Gut.

[17]  C. Knauf,et al.  Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia , 2007, Diabetologia.

[18]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[19]  J. Rutledge,et al.  Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[20]  L. Deldicque,et al.  Inulin-type fructans with prebiotic properties counteract GPR43 overexpression and PPARγ-related adipogenesis in the white adipose tissue of high-fat diet-fed mice. , 2011, The Journal of nutritional biochemistry.

[21]  Ying Gao,et al.  Bioinformatics Applications Note Sequence Analysis Cd-hit Suite: a Web Server for Clustering and Comparing Biological Sequences , 2022 .

[22]  Ting Wang,et al.  The gut microbiota as an environmental factor that regulates fat storage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Andreas Wilke,et al.  phylogenetic and functional analysis of metagenomes , 2022 .

[24]  L. Fulton,et al.  Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. , 2008, Cell host & microbe.

[25]  R. P. Ross,et al.  Correlation of rRNA gene amplicon pyrosequencing and bacterial culture for microbial compositional analysis of faecal samples from elderly Irish subjects , 2011, Journal of applied microbiology.

[26]  I. Pereira,et al.  Sulfate-reducing bacteria in human feces and their association with inflammatory bowel diseases. , 2002, FEMS microbiology ecology.

[27]  G. Wilcox.  Insulin and insulin resistance. , 2005, The Clinical biochemist. Reviews.

[28]  C. Glass,et al.  Macrophages, inflammation, and insulin resistance. , 2010, Annual review of physiology.

[29]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[30]  A. Tarnawski,et al.  Mechanism of extracellular calcium regulation of intestinal epithelial tight junction permeability: Role of cytoskeletal involvement , 2000, Microscopy research and technique.

[31]  Patrice D Cani,et al.  Interaction between obesity and the gut microbiota: relevance in nutrition. , 2011, Annual review of nutrition.

[32]  R. Knight,et al.  Error-correcting barcoded primers for pyrosequencing hundreds of samples in multiplex , 2008, Nature Methods.

[33]  R. Welch,et al.  RTX toxin structure and function: a story of numerous anomalies and few analogies in toxin biology. , 2001, Current topics in microbiology and immunology.

[34]  D. Drucker,et al.  Improvement of Glucose Tolerance and Hepatic Insulin Sensitivity by Oligofructose Requires a Functional Glucagon-Like Peptide 1 Receptor , 2006, Diabetes.

[35]  H. Nagamune,et al.  Intermedilysin, a novel cytotoxin specific for human cells secreted by Streptococcus intermedius UNS46 isolated from a human liver abscess , 1996, Infection and immunity.

[36]  Patrice D Cani,et al.  Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats* , 2004, British Journal of Nutrition.

[37]  Michael A McGuckin,et al.  Mucolytic Bacteria With Increased Prevalence in IBD Mucosa Augment In Vitro Utilization of Mucin by Other Bacteria , 2010, The American Journal of Gastroenterology.

[38]  Patrice D Cani,et al.  Increasing endogenous 2‐arachidonoylglycerol levels counteracts colitis and related systemic inflammation , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  Nathalie M. Delzenne,et al.  Prebiotic effects: metabolic and health benefits , 2010, British Journal of Nutrition.

[40]  Masahito Watanabe,et al.  IN MICE , 2009 .

[41]  Y. Sanz,et al.  Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women , 2010, British Journal of Nutrition.

[42]  J. Tiedje,et al.  Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy , 2007, Applied and Environmental Microbiology.

[43]  R. Bibiloni,et al.  Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice , 2008, Diabetes.

[44]  F. Bäckhed,et al.  Obesity alters gut microbial ecology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Jeffrey I. Gordon,et al.  Mechanisms underlying the resistance to diet-induced obesity in germ-free mice , 2007, Proceedings of the National Academy of Sciences.

[46]  W. D. de Vos,et al.  Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults , 2009, Environmental microbiology.

[47]  David Hernández,et al.  Study of inter- and intra-individual variations in the salivary microbiota , 2010, BMC Genomics.

[48]  James R. Cole,et al.  The Ribosomal Database Project: improved alignments and new tools for rRNA analysis , 2008, Nucleic Acids Res..

[49]  M. Crowell,et al.  Human gut microbiota in obesity and after gastric bypass , 2009, Proceedings of the National Academy of Sciences.

[50]  Youfang Cao,et al.  Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice , 2010, The ISME Journal.

[51]  Patrice D Cani,et al.  Dietary non-digestible carbohydrates promote L-cell differentiation in the proximal colon of rats , 2007, British Journal of Nutrition.

[52]  J. Stockman,et al.  Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5 , 2012 .

[53]  Robert C. Edgar,et al.  MUSCLE: multiple sequence alignment with high accuracy and high throughput. , 2004, Nucleic acids research.

[54]  P. Turnbaugh,et al.  Microbial ecology: Human gut microbes associated with obesity , 2006, Nature.