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Gastroenterology. 2018 Nov 13. pii: S0016-5085(18)35259-4. doi: 10.1053/j.gastro.2018.11.017. [Epub ahead of print]

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

Author information

1
Department of Surgery, Vanderbilt University Medical Center, Nashville, TN.
2
Department of Cancer Biology, Vanderbilt University, Nashville, TN.
3
Department of Surgery, Vanderbilt University Medical Center, Nashville, TN. Electronic address: robb.flynn@vanderbilt.edu.

Abstract

BACKGROUND AND 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, though parallel changes in body weight and other confounding variables limits this interpretation.

METHODS:

Global G protein-coupled bile acid receptor-1 null (Tgr5-/-) and intestinal-specific farnesoid X receptor null (FxrΔ/E) 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 bile diversion to the ileum (GB-IL).

RESULTS:

GB-IL induced weight loss and improved oral glucose tolerance in HFD-fed Tgr5-/-, but not FxrΔ/E mice, 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 Ex-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.

KEYWORDS:

glucagon-like polypeptide 1 (Glp-1); gut microbiome; lymph fistula; metabolic surgery

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