The Role of Gut Microbiota in Obesity and Type 2 and Type 1 Diabetes Mellitus: New Insights into “Old” Diseases

The investigation of the human microbiome is the most rapidly expanding field in biomedicine. Early studies were undertaken to better understand the role of microbiota in carbohydrate digestion and utilization. These processes include polysaccharide degradation, glycan transport, glycolysis, and short-chain fatty acid production. Recent research has demonstrated that the intricate axis between gut microbiota and the host metabolism is much more complex. Gut microbiota—depending on their composition—have disease-promoting effects but can also possess protective properties. This review focuses on disorders of metabolic syndrome, with special regard to obesity as a prequel to type 2 diabetes, type 2 diabetes itself, and type 1 diabetes. In all these conditions, differences in the composition of the gut microbiota in comparison to healthy people have been reported. Mechanisms of the interaction between microbiota and host that have been characterized thus far include an increase in energy harvest, modulation of free fatty acids—especially butyrate—of bile acids, lipopolysaccharides, gamma-aminobutyric acid (GABA), an impact on toll-like receptors, the endocannabinoid system and “metabolic endotoxinemia” as well as “metabolic infection.” This review will also address the influence of already established therapies for metabolic syndrome and diabetes on the microbiota and the present state of attempts to alter the gut microbiota as a therapeutic strategy.

[1]  J. Bouma,et al.  Regulation of the intestinal mucin MUC2 expression by short chain fatty acids: implications for epithelial protection , 2009, The Biochemical journal.

[2]  C. Hampe,et al.  Probiotic strains and mechanistic insights for the treatment of type 2 diabetes , 2017, Endocrine.

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

[4]  T. Matsuzaki,et al.  Prevention of onset in an insulin‐dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei , 1997, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

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

[6]  D. Benaiges,et al.  Obesity and type 1 diabetes mellitus management. , 2015, Minerva endocrinologica.

[7]  H. Lochs,et al.  Spatial Organization and Composition of the Mucosal Flora in Patients with Inflammatory Bowel Disease , 2005, Journal of Clinical Microbiology.

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

[9]  M. Asghari-Jafarabadi,et al.  Probiotic yogurt improves antioxidant status in type 2 diabetic patients. , 2012, Nutrition.

[10]  P. Volchkov,et al.  Microbiota regulates type 1 diabetes through Toll-like receptors , 2015, Proceedings of the National Academy of Sciences.

[11]  A. Benson,et al.  Long term effect of gut microbiota transfer on diabetes development. , 2014, Journal of autoimmunity.

[12]  Na-Ri Shin,et al.  An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice , 2013, Gut.

[13]  A. Rissanen,et al.  Bacterial Endotoxin Activity in Human Serum Is Associated With Dyslipidemia, Insulin Resistance, Obesity, and Chronic Inflammation , 2011, Diabetes Care.

[14]  H. Siljander,et al.  Early childhood infections precede development of beta‐cell autoimmunity and type 1 diabetes in children with HLA‐conferred disease risk , 2018, Pediatric diabetes.

[15]  R. Ley,et al.  Innate immunity and intestinal microbiota in the development of Type 1 diabetes , 2008, Nature.

[16]  K. Ramasamy,et al.  Probiotics for the management of type 2 diabetes mellitus: A systematic review and meta-analysis. , 2016, Diabetes research and clinical practice.

[17]  D. Jacobs,et al.  Comparison of body mass index, waist circumference, and waist/hip ratio in predicting incident diabetes: a meta-analysis. , 2007, Epidemiologic reviews.

[18]  E. Bonifacio,et al.  Primary Dietary Intervention Study to Reduce the Risk of Islet Autoimmunity in Children at Increased Risk for Type 1 Diabetes , 2011, Diabetes Care.

[19]  P. Hawkins,et al.  SCFAs Induce Mouse Neutrophil Chemotaxis through the GPR43 Receptor , 2011, PloS one.

[20]  R. Savkur,et al.  Regulation of carbohydrate metabolism by the farnesoid X receptor. , 2005, Endocrinology.

[21]  M. Atkinson,et al.  γ-Aminobutyric Acid Regulates Both the Survival and Replication of Human β-Cells , 2013, Diabetes.

[22]  Mathieu Almeida,et al.  Dietary intervention impact on gut microbial gene richness , 2013, Nature.

[23]  Jennifer C. Drew,et al.  Toward defining the autoimmune microbiome for type 1 diabetes , 2011, The ISME Journal.

[24]  S. Karaki,et al.  Expression of the short-chain fatty acid receptor, GPR43, in the human colon , 2008, Journal of Molecular Histology.

[25]  G. Kiyan,et al.  Catheter-related Saccharomyces cerevisiae Fungemia Following Saccharomyces boulardii Probiotic Treatment: In a child in intensive care unit and review of the literature , 2017, Medical mycology case reports.

[26]  J. Neu,et al.  Lactobacillus johnsonii N6.2 Mitigates the Development of Type 1 Diabetes in BB-DP Rats , 2010, PloS one.

[27]  Y. Jang,et al.  Standards of Medical Care in Diabetes-2010 by the American Diabetes Association: Prevention and Management of Cardiovascular Disease , 2010 .

[28]  Richard A. Flavell,et al.  Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity , 2012, Nature.

[29]  Xin-Hua Xiao,et al.  Imbalance of Fecal Microbiota at Newly Diagnosed Type 1 Diabetes in Chinese Children , 2016, Chinese medical journal.

[30]  Leah M. Feazel,et al.  Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity , 2013, Science.

[31]  Tommi Vatanen,et al.  Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans , 2016, Cell.

[32]  U. Ijaz,et al.  Host–microbiome interactions in human type 2 diabetes following prebiotic fibre (galacto-oligosaccharide) intake , 2016, British Journal of Nutrition.

[33]  G. Casella,et al.  Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model , 2009, The ISME Journal.

[34]  R. Munford.  Endotoxemia—menace, marker, or mistake? , 2016, Journal of leukocyte biology.

[35]  W. Scheppach,et al.  The butyrate story: old wine in new bottles? , 2004, Current opinion in clinical nutrition and metabolic care.

[36]  R. Paroni,et al.  Increased intestinal permeability precedes clinical onset of type 1 diabetes , 2006, Diabetologia.

[37]  E. Zoetendal,et al.  Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. , 2012, Gastroenterology.

[38]  M. Marinaro,et al.  Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse , 2005, Diabetologia.

[39]  L. Wicker,et al.  Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse , 1987, The Journal of experimental medicine.

[40]  J. Ilonen,et al.  A six‐fold gradient in the incidence of type 1 diabetes at the eastern border of Finland , 2005, Annals of medicine.

[41]  J. Neel.  Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? , 1962, American journal of human genetics.

[42]  Jun Wang,et al.  Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota , 2015, Nature.

[43]  H. Tilg,et al.  Microbiota and diabetes: an evolving relationship , 2014, Gut.

[44]  M. Nieuwdorp,et al.  Fecal microbiota transplantation in metabolic syndrome: History, present and future , 2017, Gut microbes.

[45]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[46]  J. Clemente,et al.  Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice , 2013, Science.

[47]  C. Verchere,et al.  Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion? , 2016, Trends in Endocrinology & Metabolism.

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

[49]  R. Burcelin,et al.  Metagenome and metabolism: the tissue microbiota hypothesis , 2013, Diabetes, obesity & metabolism.

[50]  M. Neumann,et al.  Butyrate Inhibits Leukocyte Adhesion to Endothelial Cells via Modulation of VCAM-1 , 2004, Inflammatory bowel diseases.

[51]  P. Renshaw,et al.  [Detection, evaluation, and treatment of high blood cholesterol in adults]. , 2001, Revista panamericana de salud publica = Pan American journal of public health.

[52]  Tommi Vatanen,et al.  The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. , 2015, Cell host & microbe.

[53]  P. Brigidi,et al.  Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians , 2010, PloS one.

[54]  J. Doré,et al.  Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept , 2011, Diabetologia.

[55]  P. Sansonetti,et al.  Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment , 2011, EMBO molecular medicine.

[56]  H. Siljander,et al.  The role of the intestinal microbiota in type 1 diabetes mellitus , 2016, Nature Reviews Endocrinology.

[57]  T. Dinan,et al.  Gut microbiota, obesity and diabetes , 2016, Postgraduate Medical Journal.

[58]  R. Xavier,et al.  Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 , 2009, Nature.

[59]  C. Doglioni,et al.  Duodenal Mucosa of Patients With Type 1 Diabetes Shows Distinctive Inflammatory Profile and Microbiota , 2017, The Journal of clinical endocrinology and metabolism.

[60]  Christophe Benoist,et al.  Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. , 2010, Immunity.

[61]  P. Bork,et al.  Richness of human gut microbiome correlates with metabolic markers , 2013, Nature.

[62]  M. Nieuwdorp,et al.  Intestinal microbiota and faecal transplantation as treatment modality for insulin resistance and type 2 diabetes mellitus , 2014, Clinical and experimental immunology.

[63]  Rob Knight,et al.  Defining the human microbiome. , 2012, Nutrition reviews.

[64]  J. Tuomilehto,et al.  Do microbes have a causal role in type 1 diabetes? , 2005, Medical science monitor : international medical journal of experimental and clinical research.

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

[66]  H. Harmsen,et al.  Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? , 2006, Diabetologia.

[67]  Yiming Li,et al.  GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes , 2011, Proceedings of the National Academy of Sciences.

[68]  J. Ilonen,et al.  Fecal Microbiota Composition Differs Between Children With β-Cell Autoimmunity and Those Without , 2013, Diabetes.

[69]  A. Schwiertz,et al.  Microbiota and SCFA in Lean and Overweight Healthy Subjects , 2010, Obesity.

[70]  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.

[71]  Richard A. Flavell,et al.  NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis , 2011, Cell.

[72]  J. Danska,et al.  Microbiome manipulation modifies sex-specific risk for autoimmunity , 2014, Gut microbes.

[73]  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.

[74]  C. Kelly,et al.  Weight Gain After Fecal Microbiota Transplantation , 2015, Open forum infectious diseases.

[75]  E. Want,et al.  Systemic gut microbial modulation of bile acid metabolism in host tissue compartments , 2010, Proceedings of the National Academy of Sciences.

[76]  F. Bäckhed,et al.  Host-Bacterial Mutualism in the Human Intestine , 2005, Science.

[77]  F. Bäckhed,et al.  Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis. , 2016, Cell metabolism.

[78]  Lee M. Kaplan,et al.  Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and Adiposity , 2013, Science Translational Medicine.

[79]  A. Rudensky,et al.  Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation , 2013, Nature.

[80]  R. Holman,et al.  Metformin as first choice in oral diabetes treatment: the UKPDS experience. , 2007, Journees annuelles de diabetologie de l'Hotel-Dieu.

[81]  F. Bäckhed,et al.  Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits , 2014, Cell.

[82]  B. Beutler.  TLRs and innate immunity. , 2009, Blood.

[83]  Jarno Honkanen,et al.  Modulation of Type 1 Diabetes Risk by the Intestinal Microbiome , 2017, Current Diabetes Reports.

[84]  A. M. Habib,et al.  Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein–Coupled Receptor FFAR2 , 2012, Diabetes.

[85]  S. Anderson,et al.  Shotgun DNA sequencing using cloned DNase I-generated fragments , 1981, Nucleic Acids Res..

[86]  Jens Roat Kultima,et al.  Disentangling the effects of type 2 diabetes and metformin on the human gut microbiota , 2015, Nature.

[87]  Hayyoung Lee,et al.  Crystal Structure of the TLR4-MD-2 Complex with Bound Endotoxin Antagonist Eritoran , 2007, Cell.

[88]  D. Wishart,et al.  Recombinant Incretin-Secreting Microbe Improves Metabolic Dysfunction in High-Fat Diet Fed Rodents , 2017, Scientific Reports.

[89]  B. Balkau,et al.  Blood Microbiota Dysbiosis Is Associated with the Onset of Cardiovascular Events in a Large General Population: The D.E.S.I.R. Study , 2013, PloS one.

[90]  P. Rosenstiel,et al.  G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation1 , 2009, The Journal of Immunology.

[91]  F. Hendijani,et al.  Effects of probiotic supplementation in patients with type 2 diabetes: systematic review and meta-analysis. , 2016, Nutrition reviews.

[92]  W. D. de Vos,et al.  Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study , 2017, PloS one.

[93]  Olli Simell,et al.  Gut Microbiome Metagenomics Analysis Suggests a Functional Model for the Development of Autoimmunity for Type 1 Diabetes , 2011, PloS one.

[94]  I. Kaji,et al.  Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. , 2008, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[95]  T. Willson,et al.  Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. , 2001, Molecular endocrinology.

[96]  R. Medzhitov,et al.  The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition , 2014, Proceedings of the National Academy of Sciences.

[97]  Jacobo de la Cuesta-Zuluaga,et al.  Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid–Producing Microbiota in the Gut , 2016, Diabetes Care.

[98]  A. Gustafsson,et al.  Lipopolysaccharide associates with pro-atherogenic lipoproteins in periodontitis patients , 2008, Innate immunity.

[99]  A. Scheen.  Pharmacological management of type 2 diabetes: what’s new in 2017? , 2017, Expert review of clinical pharmacology.

[100]  Xin Wang,et al.  Butyrate Enhances Intestinal Epithelial Barrier Function via Up-Regulation of Tight Junction Protein Claudin-1 Transcription , 2012, Digestive Diseases and Sciences.

[101]  J. Neu,et al.  Inhibition of Type 1 Diabetes Correlated to a Lactobacillus johnsonii N6.2-Mediated Th17 Bias , 2011, The Journal of Immunology.

[102]  J. Auwerx,et al.  Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation , 2006, Nature.

[103]  Austin G. Davis-Richardson,et al.  Towards a functional hypothesis relating anti-islet cell autoimmunity to the dietary impact on microbial communities and butyrate production , 2016, Microbiome.

[104]  C. Yau,et al.  The Influence of the Microbiome on Type 1 Diabetes , 2017, The Journal of Immunology.

[105]  A. López-Cepero,et al.  Association of the Intestinal Microbiota and Obesity. , 2015, Puerto Rico health sciences journal.

[106]  Huihua Xia,et al.  Effects of Acarbose on the Gut Microbiota of Prediabetic Patients: A Randomized, Double-blind, Controlled Crossover Trial , 2017, Diabetes Therapy.

[107]  V. Salomaa,et al.  Endotoxemia Is Associated With an Increased Risk of Incident Diabetes , 2011, Diabetes Care.

[108]  A. Signore,et al.  NOD mouse colonies around the world--recent facts and figures. , 1993, Immunology today.

[109]  Myung-Shik Lee,et al.  Gut Microbiota and Metabolic Disorders , 2015, Diabetes & metabolism journal.

[110]  J. Tap,et al.  Differential Adaptation of Human Gut Microbiota to Bariatric Surgery–Induced Weight Loss , 2010, Diabetes.

[111]  T. Junt,et al.  Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis , 2014, Nature Medicine.

[112]  Aly A. Khan,et al.  Gender bias in autoimmunity is influenced by microbiota. , 2013, Immunity.

[113]  L. Wen,et al.  The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. , 2016, Journal of autoimmunity.

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

[115]  R. Sato,et al.  Bile Acid Reduces the Secretion of Very Low Density Lipoprotein by Repressing Microsomal Triglyceride Transfer Protein Gene Expression Mediated by Hepatocyte Nuclear Factor-4* , 2004, Journal of Biological Chemistry.

[116]  E. Fish,et al.  SeXX matters in immunity. , 2014, Trends in immunology.

[117]  O. Woolcott,et al.  Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases , 2017, Current Diabetes Reports.

[118]  Evgeni Levin,et al.  Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. , 2017, Cell metabolism.

[119]  W. Rathmann,et al.  Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study , 2015, Diabetologia.

[120]  P. Vandamme,et al.  Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives , 2011, Gut.

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

[122]  Austin G. Davis-Richardson,et al.  Compromised Gut Microbiota Networks in Children With Anti-Islet Cell Autoimmunity , 2014, Diabetes.

[123]  J. March,et al.  Secretion of Insulinotropic Proteins by Commensal Bacteria: Rewiring the Gut To Treat Diabetes , 2008, Applied and Environmental Microbiology.

[124]  Qiang Feng,et al.  A metagenome-wide association study of gut microbiota in type 2 diabetes , 2012, Nature.

[125]  Xiao-Ming Mao,et al.  Safety and efficacy of acarbose in the treatment of diabetes in Chinese patients , 2014, Therapeutics and clinical risk management.

[126]  Glenn R. Gibson,et al.  The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic , 2014 .

[127]  Fredrik H. Karlsson,et al.  Gut metagenome in European women with normal, impaired and diabetic glucose control , 2013, Nature.

[128]  J. Lederberg,et al.  `Ome Sweet `Omics--A Genealogical Treasury of Words , 2001 .

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

[130]  M. Roberfroid.  Prebiotics and synbiotics: concepts and nutritional properties , 1998, British Journal of Nutrition.

[131]  S. Sørensen,et al.  Gut Microbiota in Human Adults with Type 2 Diabetes Differs from Non-Diabetic Adults , 2010, PloS one.

[132]  G. Tsujimoto,et al.  The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43 , 2013, Nature Communications.

[133]  J. March,et al.  Engineered Commensal Bacteria Reprogram Intestinal Cells Into Glucose-Responsive Insulin-Secreting Cells for the Treatment of Diabetes , 2015, Diabetes.