Megamonas hypermegale with indole-3-lactic acid-producing capacity ameliorates hepatic fibrosis

Hepatic fibrosis lacks effective direct antifibrotic therapy. Human V3-V4 16S rRNA profiling identified a sequence feature provisionally assigned to M. hypermegale that was depleted in hepatic fibrosis; subsequent functional experiments used a cultured M. hypermegale strain. Administered from the onset of fibrosis induction, oral M. hypermegale attenuated CCl₄- and DDC-induced fibrosis in preventive/early-intervention models, reduced liver injury and collagen accumulation, and partially preserved intestinal epithelial integrity. M. hypermegale-conditioned medium suppressed transforming growth factor-β-induced hepatic stellate cell (HSC) activation, with activity retained after heat treatment, proteinase K digestion, and <3-kDa fractionation. Targeted metabolomics and germ-free mono-colonization identified indole-3-lactic acid (ILA) as a prominent M. hypermegale-associated metabolite. Purified ILA reproduced the antifibrotic phenotype and inhibited HSC contractility through aryl hydrocarbon receptor (AHR)-dependent suppression of RhoA/ROCK/p-MLC2 signaling. HSC-selective Ahr knockdown in mice and CRISPR/Cas9-mediated AHR disruption in HSCs weakened these effects. Arabinoxylan increased M. hypermegale abundance and portal ILA availability in association with reduced fibrosis. Circulating ILA was decreased in patients and inversely associated with indices of liver injury and fibrosis. These findings identify an M. hypermegale-ILA-AHR pathway that restrains HSC activation and supports microbiota-metabolite-directed strategies for experimental hepatic fibrosis.