TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload

Abstract

Background & Aims As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload. Methods Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy. Results The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy. Conclusions BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions. Lay summary Through multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.

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“…5,39,40 Partly consistent with this, our data showed that the injection of an agonist of FXR (obeticholic acid) increased BA transport and reabsorption, while the injection of an antagonist of FXR (guggulsterone) decreased them. Previous studies produced contradictory results: TGR5-KO mice exhibited enhanced BA synthesis and weakened BA transport, 41,42 but Tgr5 −/− mice exhibited decreased expression of BA synthesis genes. 6 Our study also found a decreased expression of BA transport genes in the TGR5 inhibition treatment.…”

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“…The membrane-bound G protein-coupled receptor TGR5 is ubiquitously expressed in various tissues such as intestine, liver and gallbladder ( Cipriani et al, 2011 ; Bidault-Jourdainne et al, 2021 ). In contrast to FXR, TGR5 mainly binds secondary BAs.…”