Diabetes-associated microbiota in fa/fa rats is modified by Roux-en-Y gastric bypass

Roux-en-Y gastric bypass (RYGB) and duodenal jejunal bypass (DJB), two different forms of bariatric surgery, are associated with improved glucose tolerance, but it is not clear whether the gut microbiota contributes to this effect. Here we used fa/fa rats as a model of impaired glucose tolerance to investigate whether (i) the microbiota varies between fa/fa and nondiabetic fa/+ rats; (ii) the microbiota of fa/fa rats is affected by RYGB and/or DJB; and (iii) surgically induced microbiota alterations contribute to glucose metabolism. We observed a profound expansion of Firmicutes (specifically, Lactobacillus animalis and Lactobacillus reuteri) in the small intestine of diabetic fa/fa compared with nondiabetic fa/+ rats. RYGB-, but not DJB-, treated fa/fa rats exhibited greater microbiota diversity in the ileum and lower L. animalis and L. reuteri abundance compared with sham-operated fa/fa rats in all intestinal segments, and their microbiota composition resembled that of unoperated fa/+ rats. To investigate the functional role of RYGB-associated microbiota alterations, we transferred microbiota from sham- and RYGB-treated fa/fa rats to germ-free mice. The metabolic phenotype of RYGB-treated rats was not transferred by the transplant of ileal microbiota. In contrast, postprandial peak glucose levels were lower in mice that received cecal microbiota from RYGB- versus sham-operated rats. Thus, diabetes-associated microbiota alterations in fa/fa rats can be modified by RYGB, and modifications in the cecal microbiota may partially contribute to improved glucose tolerance after RYGB.

[1]  Zu-hua Gao,et al.  Intestinal adaptation and Reg gene expression induced by antidiabetic duodenal-jejunal bypass surgery in Zucker fatty rats. , 2013, American journal of physiology. Gastrointestinal and liver physiology.

[2]  Robert C. Edgar,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2001 .

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

[4]  J. Salles,et al.  Glycemic control after stomach-sparing duodenal-jejunal bypass surgery in diabetic patients with low body mass index. , 2012, Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery.

[5]  N. Stylopoulos,et al.  Reprogramming of Intestinal Glucose Metabolism and Glycemic Control in Rats After Gastric Bypass , 2013, Science.

[6]  A. Sclafani,et al.  Zucker fafa rats maintain their obese body composition ten months after jejunoileal bypass surgery. , 1982, International journal of obesity.

[7]  F. Rubino,et al.  Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1. , 2011, American journal of physiology. Endocrinology and metabolism.

[8]  S. Danova,et al.  Influence of Lactobacillus brevis 15 and Lactobacillus plantarum 13 on blood glucose and body weight in rats after high-fructose diet. , 2015, Beneficial microbes.

[9]  William A. Walters,et al.  QIIME allows analysis of high-throughput community sequencing data , 2010, Nature Methods.

[10]  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.

[11]  J. Licinio,et al.  Lipidomic profiling before and after Roux-en-Y gastric bypass in obese patients with diabetes , 2013, The Pharmacogenomics Journal.

[12]  A. Inui,et al.  Gastric bypass model in the obese rat to study metabolic mechanisms of weight loss. , 2002, The Journal of surgical research.

[13]  A. Miras,et al.  Roux-en Y Gastric Bypass Is Superior to Duodeno-Jejunal Bypass in Improving Glycaemic Control in Zucker Diabetic Fatty Rats , 2014, Obesity Surgery.

[14]  F. Rubino,et al.  Surgical control of obesity and diabetes: The role of intestinal vs. gastric mechanisms in the regulation of body weight and glucose homeostasis , 2014, Obesity.

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

[16]  Marti J. Anderson,et al.  A new method for non-parametric multivariate analysis of variance in ecology , 2001 .

[17]  R. Cooney,et al.  Roux-en-Y gastric bypass alters small intestine glutamine transport in the obese Zucker rat. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[18]  V. Tremaroli,et al.  Oral microbiota in patients with atherosclerosis. , 2015, Atherosclerosis.

[19]  B. Haas,et al.  Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. , 2011, Genome research.

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

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

[22]  L. Milone,et al.  Sleeve Gastrectomy Improves Glucose Homeostasis in Zucker Diabetic Fatty Rats , 2012, Obesity Surgery.

[23]  R. Batterham,et al.  Gut Hormone Profiles Following Bariatric Surgery Favor an Anorectic State, Facilitate Weight Loss, and Improve Metabolic Parameters , 2006, Annals of surgery.

[24]  T. Gavin,et al.  Duodenal–Jejunal Bypass Surgery Does Not Increase Skeletal Muscle Insulin Signal Transduction or Glucose Disposal in Goto–Kakizaki Type 2 Diabetic Rats , 2011, Obesity surgery.

[25]  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.

[26]  J. Marescaux,et al.  The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes , 2006, Annals of surgery.

[27]  Eoin L. Brodie,et al.  Greengenes, a Chimera-Checked 16S rRNA Gene Database and Workbench Compatible with ARB , 2006, Applied and Environmental Microbiology.

[28]  K. Clément,et al.  Metabolite Profiling Identifies Candidate Markers Reflecting the Clinical Adaptations Associated with Roux-en-Y Gastric Bypass Surgery , 2009, PloS one.

[29]  R. Seeley,et al.  Duodenal-Jejunal Exclusion Improves Glucose Tolerance in the Diabetic, Goto-Kakizaki Rat by a GLP-1 Receptor-Mediated Mechanism , 2009, Journal of Gastrointestinal Surgery.

[30]  M. Horowitz,et al.  Upregulation of intestinal glucose transporters after Roux‐en‐Y gastric bypass to prevent carbohydrate malabsorption , 2014, Obesity.

[31]  K. Polonsky,et al.  Moderate Effect of Duodenal‐Jejunal Bypass Surgery on Glucose Homeostasis in Patients With Type 2 Diabetes , 2012, Obesity.

[32]  I. Wilson,et al.  Age and Microenvironment Outweigh Genetic Influence on the Zucker Rat Microbiome , 2014, PloS one.

[33]  H. Ashrafian,et al.  Metabolic surgery profoundly influences gut microbial–host metabolic cross-talk , 2011, Gut.

[34]  V. Go,et al.  Alterations in fecal Lactobacillus and Bifidobacterium species in type 2 diabetic patients in Southern China population , 2013, Front. Physio..

[35]  R. Knight,et al.  UniFrac: a New Phylogenetic Method for Comparing Microbial Communities , 2005, Applied and Environmental Microbiology.

[36]  Er,et al.  Abundance and Diversity of Microbiota in Type 2 Diabetes and Obesity , 2013 .

[37]  Sarah L. Westcott,et al.  Development of a Dual-Index Sequencing Strategy and Curation Pipeline for Analyzing Amplicon Sequence Data on the MiSeq Illumina Sequencing Platform , 2013, Applied and Environmental Microbiology.

[38]  J. Tap,et al.  Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes. , 2013, The American journal of clinical nutrition.

[39]  N. Abumrad,et al.  The Importance of Caloric Restriction in the Early Improvements in Insulin Sensitivity After Roux-en-Y Gastric Bypass Surgery , 2010, Diabetes Care.

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

[41]  C. Bouchard,et al.  Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. , 2014, JAMA.

[42]  B. Jeanrenaud,et al.  Abnormal oral glucose tolerance in genetically obese (fa/fa) rats. , 1985, The American journal of physiology.

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

[44]  Rob Knight,et al.  PyNAST: a flexible tool for aligning sequences to a template alignment , 2009, Bioinform..

[45]  Patrice D. Cani,et al.  Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling , 2015, Cell metabolism.

[46]  Janne Nikkilä,et al.  Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. , 2010, Journal of microbiological methods.

[47]  J. Marescaux,et al.  The role of the small bowel in the regulation of circulating ghrelin levels and food intake in the obese Zucker rat. , 2005, Endocrinology.

[48]  M. Laakso,et al.  Conjugated Bile Acids Associate with Altered Rates of Glucose and Lipid Oxidation after Roux-en-Y Gastric Bypass , 2012, Obesity Surgery.

[49]  C. Bouchard,et al.  Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. , 2012, The New England journal of medicine.

[50]  M. Wong,et al.  Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters , 2012, The Pharmacogenomics Journal.

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

[52]  F. Bäckhed,et al.  Roux-en-Y Gastric Bypass Surgery Induces Early Plasma Metabolomic and Lipidomic Alterations in Humans Associated with Diabetes Remission , 2015, PloS one.

[53]  M. Kroh,et al.  Can Diabetes Be Surgically Cured? Long-Term Metabolic Effects of Bariatric Surgery in Obese Patients with Type 2 Diabetes Mellitus , 2013, Annals of surgery.