Gut Commensal Bacteria Ameliorate Liver Fibrosis by Inhibiting Macrophage M1 Polarization Through Secondary Bile...

The gut microbiota plays a critical role in regulating liver metabolism and immunity, significantly influencing hepatic inflammation and fibrogenesis. However, the mechanisms by which it modulates the progression of liver fibrosis remain unclear. This study investigated the interplay between the gut microbiota and bile acids in murine liver fibrosis. A mouse model of liver fibrosis was established via intraperitoneal injection of carbon tetrachloride. The gut microbiota was depleted using an antibiotic cocktail, as confirmed through 16S rRNA sequencing. Bile acid profiles were measured using ultra-performance liquid chromatography-tandem mass spectrometry. The effects of secondary bile acids on macrophage polarization were assessed in vivo and in vitro. Gut commensal microbiota depletion exacerbated liver inflammation and fibrosis. Concomitantly, this depletion significantly reduced microbiota-derived secondary bile acids. Notably, supplementation with deoxycholic acid markedly attenuated liver fibrosis. This protective effect was associated with the inhibition of pro-inflammatory M1 macrophage polarization. Takeda G protein-coupled receptor 5 (TGR5) activation was identified as the mechanism underlying the effect of deoxycholic acid on macrophages, as a TGR5 antagonist reversed this inhibition. Mechanistically, TGR5 activation suppressed the NF-κB pathway in macrophages via the cAMP-PKA signaling cascade, thereby inhibiting hepatic stellate cell activation. Our results demonstrate that the gut microbiota-secondary bile acid-TGR5 signaling axis plays a critical role in liver fibrosis and represents a promising therapeutic target.