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

Cellular & Molecular Immunology volume 22, pages 1414–1426 (2025)Cite this article

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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.

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Fig. 1: Gut-derived IPA exerts antifibrotic effects in vivo.
Fig. 2: IPA reveals multicellular roles in anti-fibrogenesis.
Fig. 3: IPA directly targets hepatic macrophages to drive its  antifibrotic effects.
Fig. 4: IPA modulates the AhR/NF-κB pathway to inhibit the profibrotic functions of macrophages.
Fig. 5: IPA suppresses S100A8/A9+ macrophages via AhR/NF-κB and alters sphingolipid metabolism to attenuate fibrogenesis.
Fig. 6: IPA ameliorates liver fibrosis via the macrophage-HSC axis.

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Data availability

All sequencing data generated during this study have been deposited in the Gene Expression Omnibus (GEO) database (GSE277148). The previously published human scRNA-seq datasets used in this study are available in GSE168933. The metagenomic and metabolomic data, along with the research materials referenced in this article, are available from the corresponding author upon reasonable request.

Code availability

All sequencing data generated during this study have been deposited in the Gene Expression Omnibus (GEO) database (GSE277148). The previously published human scRNA-seq datasets used in this study are available in GSE168933. The metagenomic and metabolomic data, along with the research materials referenced in this article, are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2023YFC2507500), the National Natural Science Foundation of China (82470661, 82070616, 82270636, 82100608, 82300607), the New Quality Clinical Specialties of High-end Medical Disciplinary Construction in Pudong New Area (2025-PWXZ-04) and the Talent Plan of the Shanghai Municipal Health Commission for Academic Leaders (2022XD028). We gratefully acknowledge Eastern Hepatobiliary Surgery Hospital (Navy Medical University, Shanghai, China) for supporting tissue sample determination. Figure support was provided by Figdraw.

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Author notes

  1. These authors contributed equally: Yuanyuan Luo, Yarong Hao, Chunyan Sun, Zhi Lu, Hao Wang.

Authors and Affiliations

  1. Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Yuanyuan Luo, Chunyan Sun, Yaping Guan, Lingyan Cai, Chenhong Ding, Binbin Li, Yiting Lu & Xin Zeng

  2. Department of Gastroenterology, Shanghai Changzheng Hospital, Navy Medical University, Shanghai, 200003, China

    Yarong Hao, Hao Wang, Fei Chen & Yong Lin

  3. Department of Psychological and Cognitive Sciences & Institute for Brain and Cognitive Sciences, Tsinghua University, Beijing, 100084, China

    Zhi Lu

  4. Zhejiang Hehu Technology, Hangzhou, 311121, China

    Zhi Lu

  5. Queen Marry university, Nanchang University, Nanchang, 330006, China

    Yuhan Lin

  6. Department of Pathology, Shanghai Changzheng Hospital, Navy Medical University, Shanghai, 200003, China

    Binbin Li

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Contributions

Xin Zeng and Yong Lin: designed, coordinated and supervised the study, reviewed, and edited the manuscript; Yuanyuan Luo, Yarong Hao, Chunyan Sun, Zhi Lu, and Hao Wang: original draft preparation, established the animal models, and drafted the manuscript; Yuhan Lin, Lingyan Cai, Chenhong Ding, Binbin Li, and Fei Chen, and Yiting Lu: performed the data analysis and interpretation of the data. All the authors critically revised the manuscript and approved the final version.

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Correspondence to Yong Lin or Xin Zeng.

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The authors declare no competing interests.

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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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Luo, Y., Hao, Y., Sun, C. et al. Gut-derived indole propionic acid alleviates liver fibrosis by targeting profibrogenic macrophages via the gut‒liver axis. Cell Mol Immunol 22, 1414–1426 (2025). https://doi.org/10.1038/s41423-025-01339-x

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