TLR4 regulates RORγt+ regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila

作者：Yaojiang Liu, Min Yang, Li Tang, Fengchao Wang, Shengjie Huang, Shuang Liu, Yuanyuan Lei, Sumin Wang, Zhuo Xie, Wei Wang, Xiaoyan Zhao, Bo Tang, Shiming Yang · 发表于：Microbiome · 年份：2022 · DOI：10.1186/s40168-022-01296-x · 被引用次数：262 · 研究领域：Immune Response and Inflammation、Gut microbiota and health、Immune Cell Function and Interaction

Abstract Background Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4 −/− mice were gut microbiota-dependent and aimed to identify the potential immunity modulation mechanism. Methods We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4 −/− mice to assess the influence of TLR4 on intestinal microbial ecology. 16S rRNA sequencing was performed to dissect microbial discrepancies, and dysbiosis-associated immune perturbation was investigated by flow cytometry. Akkermansia muciniphila ( A. muciniphila )-mediated immune modulation was confirmed through the T-cell transfer colitis model and bone marrow chimaera construction. Results TLR4 −/− mice experienced enhanced susceptibility to DSS-induced colitis. 16S rRNA sequencing showed notable discrepancy in the gut microbiota between WT and TLR4 −/− mice. In particular, A. muciniphila contributed most to distinguishing the two groups. The T-cell transfer c...