Lactobacillus murinus improves liver fibrosis in primary sclerosing cholangitis mice by decreasing taurocholic acid and regulating M2 macrophage polarization.

Abstract

Hepatic accumulation of bile acids (BAs) contributes to cholestasis-induced liver injury and fibrosis. Our previous studies have shown that Lactobacillus murinus ( L. murinus) alleviates liver fibrosis in primary sclerosing cholangitis (PSC) by modulating bile acid metabolism. In this study, we found that L. murinus intervention alleviated hepatic taurocholic acid (TCA) accumulation, cholestasis, and liver fibrosis in PSC mice. TCA was shown to promote liver fibrosis in PSC mice by enhancing M2 macrophage-mediated secretion of transforming growth factor beta 1 (TGF-β1). Macrophage depletion in PSC mice reduced the proportion of M2 macrophages and TGF-β1 cytokine levels, alleviating liver fibrosis. L. murinus exhibited bile salt hydrolase (BSH) activity, preferentially hydrolyzing glycine-conjugated bile acids. Furthermore, L. murinus reduced TCA reabsorption into the portal circulation by suppressing farnesoid X receptor ( Fxr) gene expression in the ileum, thereby alleviating hepatic TCA accumulation and mitigating liver fibrosis in PSC mice. These findings suggest that L. murinus mitigates PSC-associated liver fibrosis, which is associated with reduced TCA levels and regulation of M2 macrophage polarization, offering a potential therapeutic strategy for PSC.