Gut-derived indole propionic acid alleviates liver fibrosis by targeting profibrogenic macrophages via the gut‒liver axis.

Gut-derived metabolites are essential for liver fibrogenesis. The aim of this study was to determine the alteration of indole-3-propionic acid (IPA), a crucial tryptophan metabolite, in liver fibrosis and delineate the roles of enterogenic IPA in fibrogenesis. In the present study, metabolomics assays focused on tryptophan metabolism were applied to explore the decreased levels of IPA in the feces and serum of cirrhotic patients, as well as in the feces and portal vein serum of fibrotic mice. Oral IPA administration exerted strong antifibrotic effects with favorable biosafety in three fibrotic models via multicellular modulation. Multiplex immunohistochemical staining and DAOSLIMIT imaging demonstrated that gut-derived IPA was directly captured by hepatic macrophages. Macrophage-specific AhR knockout blocked the antifibrotic effect of IPA, while the therapeutic efficacy was maintained in mice with HSC- or hepatocyte-specific AhR depletion. Furthermore, IPA governed macrophage recruitment, S100A8/A9⁺ phenotype transformation and profibrotic and proinflammatory functions, resulting in amelioration of hepatic fibrogenesis. Mechanistically, IPA targeted the AhR/NF-κB/S100A8/A9 axis and AhR/SPHK2/S1P signaling to inhibit the profibrotic biological characteristics of macrophages and subsequently interrupted the profibrogenic crosstalk between macrophages and hepatic stellate cells (HSCs) in coculture systems and 3D liver spheroid models. These findings increase the understanding of the effects of enterogenic tryptophan metabolites on liver fibrogenesis via the gut‒liver axis and support the translational potential of IPA. By targeting profibrogenic macrophages, IPA could serve as a promising candidate for the clinical management of liver fibrosis.