Tryptophan catabolites from microbiota ameliorate immune-mediated hepatitis through activating aryl hydrocarbon receptor of T cells
Intestinal dysbiosis and T cell-mediated immune attack are implicated in the pathogenesis of autoimmune hepatitis (AIH). However, the mechanisms by which microbiota-derived metabolites modulate immune homeostasis in AIH remain elusive. Here, we demonstrated that microbiota-derived indole-3-carboxaldehyde (ICA) was significantly reduced in patients with AIH. Treatment with ICA restricted the activation of effector T cells by activating AhR in T lymphocytes. Nuclear translocation of AhR induced the transcription of PI3K interacting protein 1 (Pik3ip1), which inhibited the PI3K/Akt/mTOR signaling pathway. In vivo supplementation of ICA suppressed effector T cells and mitigated the tissue damage and hepatic inflammation in two mouse models of T cell-mediated hepatitis. Importantly, T cell-specific deletion of AhR abrogated the protective effects of ICA in AIH-like mouse model. Finally, administration of Lactobacillus reuteri resulted in elevated level of ICA and protected mice from liver damage. Our data suggest that ICA supplementation ameliorates immune-mediated hepatitis through agonizing AhR in T cells, presenting a promising therapeutic strategy for AIH.
Authors
- Qiaoyan Liu (ORCID: https://orcid.org/0000-0003-4621-5157)
- Yufeng Zhou (ORCID: https://orcid.org/0000-0002-6050-4951)
- Xiong Ma (ORCID: https://orcid.org/0000-0001-9616-4672)
- Bo Li (ORCID: https://orcid.org/0000-0002-4456-7303)
- Zhi Wang (ORCID: https://orcid.org/0000-0002-5276-1413)
- Rui Wang (ORCID: https://orcid.org/0000-0003-1723-4746)
- Jun Zhang (ORCID: https://orcid.org/0000-0002-6523-7573)
- Xiao Xiao (ORCID: https://orcid.org/0000-0001-6481-647X)
- Yikang Li (ORCID: https://orcid.org/0000-0002-3076-5982)
- Qi Miao (ORCID: https://orcid.org/0000-0002-4500-8140)
- Min Lian (ORCID: https://orcid.org/0000-0003-2122-1614)
- Xueying Liang
- Yiran Wei (ORCID: https://orcid.org/0009-0007-1804-2670)
- Ruqi Tang (ORCID: https://orcid.org/0000-0003-0890-9094)
- M. Eric Gershwin
- Zhengrui You
- Qixia Wang (ORCID: https://orcid.org/0000-0001-6759-530X)
Institutions
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- National Health and Family Planning Commission (CN)
- Renji Hospital (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Stomatology Hospital (CN)
- State Key Laboratory of Oncogene and Related Genes (CN)
- Children's Hospital of Fudan University (CN)
- University of California, Davis (US)
Publication Details
- Journal
- Gut Microbes
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1080/19490976.2025.2557979
- Citations
- 12
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 6.93