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

Nature Chemical Biology volume 17, pages 20–29 (2021)Cite this article

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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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Fig. 1: DIO mice display improved glucose tolerance and insulin sensitivity after SG.
Fig. 2: The BA metabolite CA7S is increased in mice and humans after SG.
Fig. 3: CA7S activates TGR5 signaling and increases Tgr5 expression.
Fig. 4: Acute CA7S administration induces GLP-1 and reduces serum glucose levels in vivo.
Fig. 5: CA7S gavage induces GLP-1 and improves glucose tolerance in vivo via TGR5.
Fig. 6: CA7S displays anti-diabetic effects in a chronic setting and does not affect gallbladder filling.

Data availability

All data generated or analyzed during this study are included in this article and its Supplementary information and extended data files.

Code availability

No custom code or mathematical algorithms were used in this study.

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Acknowledgements

We thank members of the Devlin, Sheu, Clardy and Banks labs (HMS) for helpful discussions and advice. We would like to acknowledge the Blacklow and Kruse labs for help with equipment and reagents, and the BWH mouse facility. We would like to thank K. Schoonjans (Ecole polytechnique fédérale de Lausanne) for the FXR reporter plasmid. We thank the human patients who participated in the present study. This work was supported by a KL2 award from Harvard Catalyst (no. 4Kl2TR001100-04 to E.G.S.), a pilot grant from Boston Area Diabetes and Endocrinology Research Center (BADERC) (no. NIH/NIDDK P30 DK057521 to E.G.S.), an NIH MIRA grant (no. R35 GM128618 to A.S.D.), a Blavatnik Biomedical Accelerator at Harvard University grant (to A.S.D.), a Quadrangle Fund for the Advancement and Seeding of Translational Research at Harvard Medical School (Q-FASTR) grant (to A.S.D. and E.G.S.), an American Heart Association Postdoctoral Fellowship (to S.N.C.), a HMS Department of Biological Chemistry and Molecular Pharmacology Fellowship (to S.N.C), an American College of Surgeons fellowship (to D.A.H.), an NIH T32 training grant (to D.A.H. and J.N.L), and a DRC P&F program grant from the Joslin Diabetes Center (no. P30DK036836) (to A.H.V).

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Author notes

  1. These authors contributed equally: Snehal N. Chaudhari, David A. Harris.

Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Snehal N. Chaudhari, Matthew T. Henke & A. Sloan Devlin

  2. Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    David A. Harris, Hassan Aliakbarian, James N. Luo, Renuka Subramaniam, Ashley H. Vernon, Ali Tavakkoli & Eric G. Sheu

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Contributions

A.S.D., E.G.S., S.N.C. and D.A.H. conceived the project and designed the experiments. S.N.C. performed the cell culture experiments, BA profiling, and transcriptional analyses and hormone quantifications on mouse tissues and blood. D.A.H. performed the mouse surgeries and the enteral administration in vivo experiments. H.A., R.S. and J.N.L. performed the gavages, OGTTs and lentiviral injection experiments. J.N.L. performed the chronic dosing experiments. M.T.H. performed NMR analyses. A.H.V. collected and provided the human samples. S.N.C., D.A.H., E.G.S. and A.S.D. wrote the manuscript. A.T. provided feedback and reviewed the manuscript. All authors edited and contributed to the critical review of the manuscript.

Corresponding authors

Correspondence to Eric G. Sheu or A. Sloan Devlin.

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Competing interests

CA7S is a subject of patents held by HMS and BWH on which S.N.C., D.A.H., E.G.S. and A.S.D. are inventors. A.S.D. is a consultant for Kintai Therapeutics and HP Hood. E.G.S. was previously on the scientific advisory board of Kitotech, Inc.

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Extended data

Extended Data Fig. 1 Bile acid structures.

a, Structures of bile acids in main text and figures. b, Structures of additional bile acids in Extended Data and Supplementary Information.

Extended Data Fig. 2 NMR of cholic acid-7-sulfate.

a, 1H NMR of authentic sample of cholic acid-7-sulfate (CA7S) (Cayman Chemical). b, 1H NMR of CA7S purified from the cecal contents of SG mice. Signals between 3.7 to 4.4 ppm are diagnostic of CA7S. Impurities are denoted by asterisks.

Extended Data Fig. 3 Bile acid concentrations in cecal contents of mice post-sham or post-SG.

Six weeks following surgery, cecal contents were collected from sham or SG mice after an overnight fast. Bile acids were quantified using UPLC-MS (sham, n = 12, SG, n = 15, data not marked with asterisk(s) are not significant). All bile acids with measurable concentrations above the limit of detection are shown. Tα/βMCA, tauro-alpha- and tauro-beta-muricholic acid, p = 0.53; TCA, tauro-cholic acid, p = 0.32; TγMCA, tauro-gamma-muricholic acid, p = 0.36; TωMCA, tauro-omega-muricholic acid, p = 0.68; TUDCA, tauro-ursodeoxycholic acid, p = 0.67; 7-oxo-TCDCA, 7-oxo-tauro-chenodeoxycholic acid p = 0.34; αMCA, alpha-muricholic acid, p = 0.87; βMCA, beta-muricholic acid, p = 0.59; CA, cholic acid, p = 0.28; UDCA, ursodeoxycholic acid, p = 0.85; DCA, deoxycholic acid, p = 0.48; LCA, lithocholic acid, *p = 0.02; isoLCA, isolithocholic acid *p = 0.02; 3-oxo-CA, 3-oxo-cholic acid, p = 0.08; 3-oxo-LCA, 3-oxo-lithocholic acid, p = 0.79; CDCA, chenodeoxycholic acid, *p = 0.03, two-tailed Welch’s t-test. All data are presented as mean ± SEM.

Extended Data Fig. 4 Bile acid concentrations in feces of human patients pre-SG or post-SG.

Feces were collected from patients pre-op or ~5 weeks post-op and bile acids were quantified using UPLC-MS (n = 17 patients, median 36 days after surgery, data not marked with asterisk(s) are not significant). All bile acids with measurable concentrations above the limit of detection are shown. TCDCA, tauro-chenodeoxycholic acid, p = 0.97; TDCA, tauro-deoxycholic acid, p = 0.93; CA, cholic acid, **p = 1.00×10-3; CDCA, chenodeoxycholic acid, p = 0.52; DCA, deoxycholic acid, p = 0.13; LCA, lithocholic acid, *p = 0.01; isoLCA, iso-lithocholic acid, *p = 0.03; UDCA, ursodeoxycholic acid, *p = 0.02; 3-oxo-CDCA, 3-oxo-chenodeoxycholic acid, p = 0.92; 7-oxo-CDCA, 7-oxo-chenodeoxycholic acid, p = 0.47, 3-oxo-LCA, 3-oxo-lithocholic acid, p = 0.56, two-tailed paired t-test. All data are presented as mean ± SEM.

Extended Data Fig. 5 CA7S agonizes TGR5 but not FXR, induces GLP-1 secretion, and reduces systemic glucose levels.

a, CA7S (500 µM) purified from SG mouse cecal contents induced secretion of GLP-1 in NCI-H716 cells compared to DMSO control (6 biological replicates per condition, **p = 1.00×10-3, two-tailed Welch’s t-test). b, Quantitative real time PCR analysis of expression of human TGR5 in TGR5 siRNA and negative (-) siRNA-treated NCI-H716 cells for Fig. 3b. c, CA7S induced an increase in intracellular calcium levels in NCI-H716 cells (4 biological replicates per condition, CA7S 10 µM *p = 0.03, 50 µM *p = 0.02, 100 µM **p = 1.80×10-3, 100 µM *p = 0.01, one-way ANOVA followed by Dunnett’s multiple comparisons test). d, CA7S induced secretion of GLP-1 in the presence of a physiologically relevant concentration of LCA (150 μM) (3 biological replicates per condition, DMSO (-) control vs. LCA **p = 9.90 × 10−3, CA7S vs. LCA 0.1 μM *p = 0.03, two-way ANOVA followed by Dunnett’s multiple comparisons test). e, CA7S did not induce activation of endogenous FXR in Caco-2 cells compared to (-) DMSO control. Known FXR agonist CDCA (10 µM) was used as a positive control (4 biological replicates per condition, CA7S 0.01-50 µM and 500–1000 µM not significant p = 0.99, CA7S 100 µM not significant p = 0.96, CDCA 10 µM **p = 4.60 × 10−3, one-way ANOVA followed by Dunnett’s multiple comparisons test). f, In vivo change in serum glucose upon acute enteral treatment with PBS and CA7S (PBS, n = 6; CA7S, n = 8 mice, ***p = 1.00 × 10−4, ns=not significant p = 0.63, two-tailed paired t-test). All data are presented as mean ± SEM.

Extended Data Fig. 6 Bile acid concentrations in cecal contents of mice treated enterally with CA7S.

Cecal contents were collected from mice after enteral treatment with CA7S or PBS and bile acids were quantified using UPLC-MS (PBS, n = 7, CA7S, n = 8, data not marked with asterisk(s) are not significant). All bile acids with measurable concentrations above the limit of detection are shown. Total BAs without CA7S, p = 0.50; Total bile acids (BAs), **p = 3.5 × 10−3; Tα/βMCA, tauro-alpha- and tauro-beta-muricholic acid, p = 0.88; TCA, tauro-cholic acid, p = 0.49; TωMCA, tauro-omega-muricholic acid, p = 0.68; 3-oxo-CDCA, 3-oxo-chenodeoxycholic acid p = 0.45; 7-oxo-CDCA, 7-oxo-chenodeoxycholic acid p = 0.87; αMCA, alpha-muricholic acid, p = 0.23; βMCA, beta-muricholic acid, p = 0.14; CA, cholic acid, p = 0.23; UDCA, ursodeoxycholic acid, p = 0.30; DCA, deoxycholic acid, p = 0.24; LCA, lithocholic acid, p = 0.50; TDCA, tauro-deoxycholic acid, p = 0.30; TCDCA, tauro-chenodeoxycholic acid, p = 0.31; CDCA, chenodeoxycholic acid, p = 0.43, two-tailed Welch’s t-test. All data are presented as mean ± SEM.

Extended Data Fig. 7 Bile acid concentrations in cecal contents of mice gavaged with one dose of CA7S.

Fasted DIO mice were gavaged with CA7S or PBS and cecal contents were collected from mice 5 hours post-gavage. Bile acids were quantified using UPLC-MS (n = 8 in each group, data not marked with asterisk(s) are not significant). All bile acids with measurable concentrations above the limit of detection are shown. Total BAs without CA7S, p = 0.35; Total bile acids (BAs), p = 0.06; Tα/βMCA, tauro-alpha- and tauro-beta-muricholic acid, p = 0.58; TγMCA, tauro-gamma-muricholic acid, p = 0.32; TCA, tauro-cholic acid, p = 0.13; TUDCA, tauro-ursodeoxycholic acid, p = 0.12; TCDCA, tauro-chenodeoxycholic acid, p = 0.13; CDCA, chenodeoxycholic acid, p = 0.33; αβMCA, alpha-muricholic acid and beta-muricholic acid, p = 0.96; CA, cholic acid, p = 0.38; TDCA, tauro-deoxycholic acid, p = 0.27; UDCA, ursodeoxycholic acid, p = 0.87; 3-oxo-CA, 3-oxo-cholic acid, p = 0.93; LCA, lithocholic acid, p = 0.86; DCA, deoxycholic acid, p = 0.76, two-tailed Welch’s t-test. All data are presented as mean ± SEM.

Extended Data Fig. 8 Bile acid concentrations in cecal contents of mice gavaged chronically with CA7S.

Cecal contents were collected from mice following an overnight fast after 48 days of daily gavage with CA7S or PBS. Bile acids were quantified using UPLC-MS (n = 7 in each group, data not marked with asterisk(s) are not significant). All bile acids with measurable concentrations above the limit of detection are shown. Total BAs without CA7S, p = 0.82; Total bile acids (BAs), p = 0.38; Tα/βMCA, tauro-alpha- and tauro-beta-muricholic acid, p = 0.46; TωMCA, tauro-omega-muricholic acid, p = 0.12; TγMCA, tauro-gamma-muricholic acid, p = 0.23; TCA, tauro-cholic acid, p = 0.09; TUDCA, tauro-ursodeoxycholic acid, p = 0.76; TCDCA, tauro-chenodeoxycholic acid, p = 0.17; αβMCA, alpha-muricholic acid and beta-muricholic acid, p = 0.23; CA, cholic acid, p = 0.06; TDCA, tauro-deoxycholic acid, p = 0.71; UDCA, ursodeoxycholic acid, *p = 0.01; CDCA, chenodeoxycholic acid, p = 0.06; DCA, deoxycholic acid, p = 0.23; LCA, lithocholic acid, *p = 0.04; 3-oxo-CA, 3-oxo-cholic acid, p = 0.30, two-tailed Welch’s t-test. All data are presented as mean ± SEM.

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Chaudhari, S.N., Harris, D.A., Aliakbarian, H. et al. Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects. Nat Chem Biol 17, 20–29 (2021). https://doi.org/10.1038/s41589-020-0604-z

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