Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects

  • Nat Chem Biol. 2021 Jan;17(1):20-29. doi: 10.1038/s41589-020-0604-z.
Snehal N Chaudhari   #  1 ,  David A Harris   #  2 ,  Hassan Aliakbarian  2 ,  James N Luo  2 ,  Matthew T Henke  1 ,  Renuka Subramaniam  2 ,  Ashley H Vernon  2 ,  Ali Tavakkoli  2 ,  Eric G Sheu  3 ,  A Sloan Devlin  4
Affiliations
  • 1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 2. Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 32747812 DOI: 10.1038/s41589-020-0604-z
Abstract

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography-mass spectrometry-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a Takeda G-protein receptor 5 (TGR5) agonist that increases Tgr5 expression and induces GLP-1 secretion. Furthermore, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-dependent manner. CA7S remains gut restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into the circulation. By studying changes in individual metabolites after surgery, the present study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

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