Cmtm4 deficiency exacerbates colitis by inducing gut dysbiosis and S100A8/9 expression

Qiao Meng; Jing Ning; Jingjing Lu; Jing Zhang; Ming Zu; Jing Zhang; Xiurui Han; Huiling Zheng; Yueqing Gong; Xinyu Hao; Ying Xiong; Fang Gu; Wenling Han; Weiwei Fu; Jun Wang; Shigang Ding

doi:10.1016/j.jgg.2024.03.009

Cmtm4 deficiency exacerbates colitis by inducing gut dysbiosis and S100A8/9 expression

J Genet Genomics. 2024 Apr 2:S1673-8527(24)00062-6. doi: 10.1016/j.jgg.2024.03.009. Online ahead of print.

Authors

Qiao Meng¹, Jing Ning¹, Jingjing Lu², Jing Zhang¹, Ming Zu¹, Jing Zhang¹, Xiurui Han¹, Huiling Zheng¹, Yueqing Gong¹, Xinyu Hao¹, Ying Xiong¹, Fang Gu¹, Wenling Han³, Weiwei Fu⁴, Jun Wang⁵, Shigang Ding⁶

Affiliations

¹ Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing 100191, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
³ Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, NHC Key Laboratory of Medical Immunology (Peking University), Beijing 100191, China; Peking University Center for Human Disease Genomics, Beijing 100191, China.
⁴ Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing 100191, China. Electronic address: fuweiwei1999@163.com.
⁵ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: junwang@im.ac.cn.
⁶ Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing 100191, China. Electronic address: dingshigang222@163.com.

PMID: 38575111
DOI: 10.1016/j.jgg.2024.03.009

Abstract

The dysfunction of innate immunity components is one of the major drivers for ulcerative colitis (UC), and increasing reports indicate that the gut microbiome serves as an intermediate between genetic mutations and UC development. Here, we find that the IL-17 receptor subunit, CMTM4, is reduced in UC patients and dextran sulfate sodium (DSS)-induced colitis. The deletion of CMTM4 (Cmtm4^-/-) in mice leads to a higher susceptibility to DSS-induced colitis than in wild-type, and the gut microbiome significantly changes in composition. The causal role of the gut microbiome is confirmed with a cohousing experiment. We further identify that S100a8/9 is significantly up-regulated in Cmtm4^-/- colitis, with the block of its receptor RAGE that reverses the phenotype associated with the CMTM4 deficiency. CMTM4 deficiency rather suppresses S100a8/9 expression in vitro via the IL17 pathway, further supporting that the elevation of S100a8/9 in vivo is most likely a result of microbial dysbiosis. Taken together, the results suggest that CMTM4 is involved in the maintenance of intestinal homeostasis, suppression of S100a8/9, and prevention of colitis development. Our study further shows CMTM4 as a crucial innate immunity component, confirming its important role in the UC development and providing insights into potential targets for the development of future therapies.

Keywords: CMTM4; Gut microbiota; IL-17 receptor C (IL-17RC; S100a8/9; Ulcerative colitis.