Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.

Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR
Gastroenterology. 2019 156 (4): 1041-1051.e4

PMID: 30445014 · PMCID: PMC6409186 · DOI:10.1053/j.gastro.2018.11.017

BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.

METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.

RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.

CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.

Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (25)

Anastomosis, Surgical Animals Anticholesteremic Agents Bariatric Surgery Bile Acids and Salts Blood Glucose Cholestyramine Resin Diet, High-Fat Gallbladder Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide 1 Glucose Tolerance Test Ileum Insulin Resistance Intestines Lymph Male Mice Mice, Inbred C57BL Mice, Knockout Receptors, Cytoplasmic and Nuclear Receptors, G-Protein-Coupled Signal Transduction Verrucomicrobia Weight Loss

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