Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.The authors examine the effects of antidiabetic medication on the gut microbiome and bile acid composition and show that these data can be used to stratify treatment regimens for type 2 diabetes.

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

[2]  M. Kanehisa,et al.  BlastKOALA and GhostKOALA: KEGG Tools for Functional Characterization of Genome and Metagenome Sequences. , 2016, Journal of molecular biology.

[3]  Wen–ying Yang,et al.  Efficacy of acarbose and metformin in newly diagnosed type 2 diabetes patients stratified by HbA1c levels , 2016, Journal of diabetes.

[4]  Wenying Yang,et al.  Standards of care for type 2 diabetes in China , 2016, Diabetes/metabolism research and reviews.

[5]  D. Accili,et al.  Human Insulin Resistance Is Associated With Increased Plasma Levels of 12α-Hydroxylated Bile Acids , 2013, Diabetes.

[6]  Timothy M Willson,et al.  Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[7]  David Torrents,et al.  Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug , 2017, Nature Medicine.

[8]  C. Hill,et al.  Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut , 2014, Proceedings of the National Academy of Sciences.

[9]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[10]  B. Fielding,et al.  Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. , 2008, Progress in lipid research.

[11]  Qiang Feng,et al.  The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment , 2015, Nature Medicine.

[12]  Dae-Joong Kang,et al.  Bile salt biotransformations by human intestinal bacteria Published, JLR Papers in Press, November 18, 2005. , 2006, Journal of Lipid Research.

[13]  S. Strom,et al.  Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α‐hydroxylase gene expression , 2009, Hepatology.

[14]  P. Bork,et al.  Enterotypes of the human gut microbiome , 2011, Nature.

[15]  S. Feighner,et al.  Lactobacilli and bile salt hydrolase in the murine intestinal tract , 1989, Applied and environmental microbiology.

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

[17]  S. Lynch,et al.  The Human Intestinal Microbiome in Health and Disease. , 2016, The New England journal of medicine.

[18]  2011 Clinical Practice Guidelines for Type 2 Diabetes in Korea , 2011 .

[19]  H. Lebovitz alpha-Glucosidase inhibitors. , 1997, Endocrinology and metabolism clinics of North America.

[20]  J. Gordon,et al.  Metabolic niche of a prominent sulfate-reducing human gut bacterium , 2013, Proceedings of the National Academy of Sciences.

[21]  J. Suez,et al.  Personalized microbiome‐based approaches to metabolic syndrome management and prevention , 2017, Journal of diabetes.

[22]  F. Rubino,et al.  Bariatric surgery versus conventional medical therapy for type 2 diabetes. , 2012, The New England journal of medicine.

[23]  Fredrik H. Karlsson,et al.  Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation , 2015, Cell metabolism.

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

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

[26]  C. M. Wood,et al.  Absorption of short-chain fatty acids by the colon. , 1980, Gastroenterology.

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

[28]  E. Ferrannini,et al.  Increased Bile Acid Synthesis and Deconjugation After Biliopancreatic Diversion , 2015, Diabetes.

[29]  J. Chiang,et al.  Bile Acid Signaling in Metabolic Disease and Drug Therapy , 2014, Pharmacological Reviews.

[30]  Wenying Yang,et al.  Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial. , 2014, The lancet. Diabetes & endocrinology.

[31]  Executive Summary: Standards of Medical Care in Diabetes—2012 , 2011, Diabetes Care.

[32]  S. Lai,et al.  Plasma glucose and hemoglobin A1c for the detection of diabetes in Chinese adults , 2016, Journal of diabetes.

[33]  M. Morotomi,et al.  Absence of cholic acid 7 alpha-dehydroxylase activity in the strains of Lactobacillus and Bifidobacterium. , 1994, Journal of dairy science.

[34]  Christopher E. McKinlay,et al.  Rethinking "enterotypes". , 2014, Cell host & microbe.

[35]  Leo Lahti,et al.  Fat, Fiber and Cancer Risk in African Americans and Rural Africans , 2015, Nature Communications.

[36]  E. Deitch,et al.  The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. , 1990, Archives of surgery.

[37]  Weiqing Wang,et al.  Postprandial glucose, insulin and incretin responses to different carbohydrate tolerance tests , 2015, Journal of diabetes.

[38]  V. Tremaroli,et al.  Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. , 2015, Cell host & microbe.

[39]  S. Kahn,et al.  Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future , 2014, The Lancet.

[40]  J. Raes,et al.  Quantitative assessment of protein function prediction from metagenomics shotgun sequences , 2007, Proceedings of the National Academy of Sciences.

[41]  Ke Ma,et al.  Farnesoid X receptor is essential for normal glucose homeostasis. , 2006, The Journal of clinical investigation.

[42]  Céline Gheeraert,et al.  Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. , 2014, The Journal of clinical investigation.

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

[44]  V. Basevi,et al.  Standards of Medical Care in Diabetes—2012 , 2011, Diabetes Care.

[45]  Anna Castiglione,et al.  The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population , 2006, BMC gastroenterology.

[46]  M. Fischer,et al.  A liquid chromatography-tandem mass spectrometry-based method for the simultaneous determination of hydroxy sterols and bile acids. , 2014, Journal of chromatography. A.

[47]  Alexandros Stamatakis,et al.  Metagenomic species profiling using universal phylogenetic marker genes , 2013, Nature Methods.

[48]  F. Bushman,et al.  Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes , 2011, Science.

[49]  P. Hylemon,et al.  Bile acids and the gut microbiome , 2014, Current opinion in gastroenterology.

[50]  Francisco Guarner,et al.  The gut microbiota in IBD , 2012, Nature Reviews Gastroenterology &Hepatology.

[51]  R. Hanson,et al.  The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. , 2000, Diabetes care.

[52]  H. Putter,et al.  Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial , 2010, The Lancet.

[53]  D. A. De-Souza,et al.  Intestinal permeability and systemic infections in critically ill patients: Effect of glutamine* , 2005, Critical care medicine.

[54]  I. Perry,et al.  Sociodemographic, health and lifestyle predictors of poor diets , 2011, Public Health Nutrition.

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

[56]  Executive Summary: Standards of Medical Care in Diabetes—2008 , 2008, Diabetes Care.

[57]  K. Clément,et al.  The importance of the gut microbiota after bariatric surgery , 2012, Nature Reviews Gastroenterology &Hepatology.

[58]  Jens Roat Kultima,et al.  An integrated catalog of reference genes in the human gut microbiome , 2014, Nature Biotechnology.

[59]  I. Albert,et al.  Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. , 2015, The Journal of clinical investigation.

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

[61]  P. Bork,et al.  Human gut microbes impact host serum metabolome and insulin sensitivity , 2016, Nature.

[62]  M. Patti,et al.  Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin. , 2014, The Journal of clinical endocrinology and metabolism.

[63]  Huijue Jia,et al.  Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention , 2017, Nature Medicine.

[64]  Hanns-Ulrich Marschall,et al.  Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. , 2016, Cell metabolism.

[65]  V. Tremaroli,et al.  FXR is a molecular target for the effects of vertical sleeve gastrectomy , 2014, Nature.

[66]  A. Moschetta,et al.  Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23 , 2015, Nature Reviews Drug Discovery.

[67]  A. Moschetta,et al.  Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. , 2014, Cell reports.

[68]  M. Laakso,et al.  Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial , 2002, The Lancet.

[69]  C. Gahan,et al.  Bile Acid Modifications at the Microbe-Host Interface: Potential for Nutraceutical and Pharmaceutical Interventions in Host Health. , 2016, Annual review of food science and technology.

[70]  P. Clifton,et al.  Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. , 2001, Physiological reviews.