Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice

Obeticholic acid (OCA) has been examined to treat non-alcoholic steatohepatitis (NASH), but has unsatisfactory antifibrotic effect and deficient responsive rate in recent phase III clinical trial. Using a prolonged western diet-feeding murine NASH model, we show that OCA-shaped gut microbiota induces lipid peroxidation and impairs its anti-fibrotic effect. Mechanically, Bacteroides enriched by OCA deconjugates tauro-conjugated bile acids to generate excessive chenodeoxycholic acid (CDCA), resulting in liver ROS accumulation. We further elucidate that OCA reduces triglycerides containing polyunsaturated fatty acid (PUFA-TGs) levels, whereas elevates free PUFAs and phosphatidylethanolamines containing PUFA (PUFA-PEs), which are susceptible to be oxidized to lipid peroxides (notably arachidonic acid (ARA)-derived 12-HHTrE), inducing hepatocyte ferroptosis and activating hepatic stellate cells (HSCs). Inhibiting lipid peroxidation with pentoxifylline (PTX) rescues anti-fibrotic effect of OCA, suggesting combination of OCA and lipid peroxidation inhibitor could be a potential antifibrotic pharmacological approach in clinical NASH-fibrosis.

Automated summary

Research has found that Obeticholic acid (OCA) has unsatisfactory antifibrotic effect and deficient responsive rate in treating non-alcoholic steatohepatitis (NASH). This is due to the gut microbiota shaped by OCA, which induces lipid peroxidation and impairs its antifibrotic effect. Additionally, OCA leads to liver ROS accumulation, causing hepatocyte ferroptosis and activation of hepatic stellate cells (HSCs). However, inhibiting lipid peroxidation can rescue the antifibrotic effect of OCA.