Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

Abstract

Backgrounds & AimsAs the bile acid (BA) pool composition is of major impact on liver pathophysiology, we studied its regulation by the BA receptor TGR5, promoting hepatoprotection against BA overload.MethodsWT, total and hepato-specific TGR5-KO, and TGR5-overexpressing mice were used in: partial and 90% extended hepatectomies (EH) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (1%)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied TGR5 impact on: BA pool composition, liver injury, regeneration and survival. Particular focus was made on gut microbiota (GM) and gallbladder (GB) function analysis. BA pool composition was analyzed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA pool was not related to BA synthesis alteration, nor to the TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and cohousing experiments. The TGR5-dependent control of GB dilatation was crucial for BA pool composition, as determined by experiments including RO treatment +/− cholecystectomy. The poor TGR5-KO post-EH survival rate, related with exacerbated peribiliary necrosis and BA overload, was improved by shifting the BA pool towards a more hydrophilic composition (CT and UDCA treatments). After either BDL or CA-enriched diet +/− cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic BA pool was correlated with an unfavorable outcome after hepatectomy.ConclusionBA pool composition is crucial for hepatoprotection in mice and humans. We point TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.Lay summaryThrough multiple in vivo experimental approaches in mice, together with a patients study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function and liver protection. We showed that the bile acid pool composition is crucial for optimal liver repair, not only in mice but also in human patients undergoing major hepatectomy.

Understanding the role of ursodeoxycholic acid and gut microbiome in non-alcoholic fatty liver disease: current evidence and perspectives

“…TGR5, also known as GPBAR1, is widely distributed in the skeletal muscle, white and brown adipocytes, ileum, and enterohepatic tissues except hepatic parenchymal cells. TGR5-dependent pathways are crucial for protecting hepatocytes from injuries, involving improvement of glucose homeostasis, gallbladder dilatation, hepatic inflammation, and energy expenditure (Carino et al, 2017;Ginos et al, 2018;Iracheta-Vellve et al, 2018;Bidault-Jourdainne et al, 2021;Wang et al, 2022). In addition, diminished TGR5 signals were found to be correlated with downregulated secondary bile acids, attributed to alterations in the abundance of bacteria involved in bile acid transformation (Spatz et al, 2021).…”

Rebuttal to: The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

“…Mechanistically, the membrane Takeda G-protein-coupled receptor activation modulates BA composition to become more hydrophilic, and thus protects against cytotoxic BA accumulation. 3 However, if the BA composition became more hydrophobic, it correlates with increased liver injury after PH in human beings and mice. 3 Mouse models with hydrophobic BA composition, including Cyp2c70 knockout and Cyp2a12/Cyp2c70 double-knockout mice, show inflammation and injury in the liver despite having a reduced overall BA concentration.…”

“…3 However, if the BA composition became more hydrophobic, it correlates with increased liver injury after PH in human beings and mice. 3 Mouse models with hydrophobic BA composition, including Cyp2c70 knockout and Cyp2a12/Cyp2c70 double-knockout mice, show inflammation and injury in the liver despite having a reduced overall BA concentration. 4 In addition, increasing evidence has shown that changes in BA composition can modulate immune responses in the liver and contribute to the pathogenesis of inflammatory diseases.…”