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. 2025 Nov;22(11):1414-1426.
doi: 10.1038/s41423-025-01339-x. Epub 2025 Sep 8.

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

Yuanyuan Luo #  1 , Yarong Hao #  2 , Chunyan Sun #  1 , Zhi Lu #  3   4 , Hao Wang #  2 , Yuhan Lin  5 , Yaping Guan  1 , Lingyan Cai  1 , Chenhong Ding  1 , Binbin Li  1   6 , Fei Chen  2 , Yiting Lu  1 , Yong Lin  7 , Xin Zeng  8
Affiliations

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

Yuanyuan Luo et al. Cell Mol Immunol. 2025 Nov.

Abstract

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.

Keywords: Gut‒liver axis; Indole-3-propionic acid; Liver fibrosis; Macrophage; Metabolomics.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval: This study protocol was conducted in accordance with the Declaration of Helsinki and approved by the Shanghai Changzheng Hospital Ethics Committee (no. 2018SL004). Written informed consent was obtained from all participants before recruitment. All the animal studies were approved by the Shanghai East Hospital Ethics Committee (no. 2023083) and conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC), ensuring the welfare and minimal suffering of the animals involved.

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