首页|Thiostrepton alleviates experimental colitis by promoting RORγt ubiquitination and modulating dysbiosis

Thiostrepton alleviates experimental colitis by promoting RORγt ubiquitination and modulating dysbiosis

扫码查看
原文链接
  • 万方数据
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 by γδ T 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.

Thiostrepton(TST)ColitisRORγtIL-17AGut microbiota

Ya Luo、Cheng Liu、Yuan Luo、Xianglian Zhang、Jing Li、Changjiang Hu、Shiming Yang

展开 >

Department of Gastroenterology,Xinqiao Hospital,Third Military Medical University,Chongqing 400037,China

Department of Gastroenterology,The Second Affiliated Hospital of Zunyi Medical University,Zunyi Medical University,Zunyi 563006,China

Department of Immunology,School of Basic Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

Department of Gastroenterology,The First Affiliated Hospital of Guangxi Medical University,Nanning 530021,China

展开 >

National Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaNatural Science Foundation of Chongqing

2018YFA050790081802460CSTB2022NSCQ-MSX0184

2023

10.1038/s41423-023-01085-y

中国免疫学杂志(英文版)
中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI
影响因子：0.731
ISSN：1672-7681
年,卷(期)：2023.20(11)
  • 50