Tryptophan catabolites from microbiota ameliorate immune-mediated hepatitis through activating aryl hydrocarbon receptor of T cells
Bo Li, Xueying Liang, Yikang Li, Rui Wang, Yiran Wei, Qiaoyan Liu, Jun Zhang, Qixia Wang, Qi Miao, Xiao Xiao, Min Lian, Zhi Wang, Yufeng Zhou, M. Eric Gershwin, Zhengrui You, Ruqi Tang, Xiong Ma
Abstract
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.