Thiostrepton alleviates experimental colitis by promoting RORγt ubiquitination and modulating dysbiosis  

作　　者：Ya Luo Cheng Liu Yuan Luo Xianglian Zhang Jing Li Changjiang Hu Shiming Yang 

机构地区：[1]Department of Gastroenterology,Xinqiao Hospital,Third Military Medical University,Chongqing,400037,China [2]Department of Gastroenterology,The Second Affiliated Hospital of Zunyi Medical University,Zunyi Medical University,Zunyi,563006,China [3]Department of Immunology,School of Basic Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [4]Department of Gastroenterology,The First Affiliated Hospital of Guangxi Medical University,Nanning,530021,China

出　　处：《Cellular & Molecular Immunology》2023年第11期1352-1366,共15页中国免疫学杂志（英文版）

基　　金：This work was supported by the National Key Research and Development Program of China(2018YFA0507900);the National Natural Science Foundation of China(81802460);the Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0184).

摘　　要：Thiostrepton(TST)is a natural antibiotic with pleiotropic properties.This study aimed to elucidate the therapeutic effect of TST on experimental colitis and identify its targets.The effect of TST on colon inflammation was evaluated in a dextran sulfate sodium(DSS)-induced colitis model and a T-cell transfer colitis model.The therapeutic targets of TST were investigated by cytokine profiling,immunophenotyping and biochemical approaches.The effect of TST on the gut microbiota and its contribution to colitis were evaluated in mice with DSS-induced colitis that were subjected to gut microbiota depletion and fecal microbiota transplantation(FMT).Alterations in the gut microbiota caused by TST were determined by 16S rDNA and metagenomic sequencing.Here,we showed that TST treatment significantly ameliorated colitis in the DSS-induced and T-cell transfer models.Specifically,TST targeted the retinoic acid-related orphan nuclear receptor RORγt to reduce the production of IL-17A byγδT cells,type 3 innate lymphoid cells(ILC3s)and Th17 cells in mice with DSS-induced colitis.Similarly,TST selectively prevented the development of Th17 cells in the T-cell transfer colitis model and the differentiation of naïve CD4^(+)T cells into Th17 cells in vitro.Mechanistically,TST induced the ubiquitination and degradation of RORγt by promoting the binding of Itch to RORγt.Moreover,TST also reversed dysbiosis to control colonic inflammation.Taken together,these results from our study describe the previously unexplored role of TST in alleviating colonic inflammation by reducing IL-17A production and modulating dysbiosis,suggesting that TST is a promising candidate drug for the treatment of IBD.

关 键 词：Thiostrepton(TST) COLITIS RORΓT IL-17A Gut microbiota 

分 类 号：R978.1[医药卫生—药品]