Phocaeicola coprocola attenuates liver fibrosis by modulating extracellular matrix remodeling

Abstract

ABSTRACT Chronic liver diseases, including metabolic dysfunction–associated steatotic liver disease (MASLD), frequently progress to liver fibrosis, yet effective antifibrotic therapies remain limited. Here, we investigated the therapeutic potential of the commensal bacterium Phocaeicola coprocola using Western diet (WD)–induced MASLD and DDC + TAA–induced fibrosis murine models. In the WD model, P. coprocola administration attenuated hepatic steatosis, reduced lipogenic gene expression, and improved metabolic and histological parameters. In contrast, in the DDC + TAA model of advanced fibrosis, P. coprocola significantly reduced cholestatic markers and fibrosis severity. Mechanistically, these antifibrotic effects occurred independently of broad suppression of inflammatory mediators or upstream TGF-β–Smad signaling, and were instead associated with selective downregulation of extracellular matrix (ECM)–related fibrogenic programs, including Col1a1, Col3a1, and Mmp2. Notably, these effects were observed even in the absence of detectable gut colonization, suggesting that stable engraftment is not required for therapeutic activity. P. coprocola also enhanced colonic epithelial barrier–related gene expression and host–microbial metabolic signaling. In humans, circulating ECM remodeling markers (PIIINP, MMP2, and TIMP1) were associated with fibrosis severity, supporting the translational relevance of ECM-targeted mechanisms. Collectively, these findings identify P. coprocola as a selective modulator of ECM remodeling that uncouples fibrotic output from upstream inflammatory signaling, highlighting its potential as a microbiome-based therapeutic strategy for liver fibrosis across multiple disease etiologies.