T-cell activation Rho GTPase-activating protein maintains intestinal homeostasis by regulating intestinal T helper cells differentiation through the gut microbiota

Ruirui He; Jianwen Chen; Ziyan Zhao; Changping Shi; Yanyun Du; Ming Yi; Lingyun Feng; Qianwen Peng; Zhihui Cui; Ru Gao; Heping Wang; Yi Huang; Zhi Liu; Chenhui Wang

doi:10.3389/fmicb.2022.1030947

T-cell activation Rho GTPase-activating protein maintains intestinal homeostasis by regulating intestinal T helper cells differentiation through the gut microbiota

Front Microbiol. 2023 Jan 10:13:1030947. doi: 10.3389/fmicb.2022.1030947. eCollection 2022.

Authors

Ruirui He^{1

2}, Jianwen Chen^{1

2}, Ziyan Zhao^{1

2}, Changping Shi³, Yanyun Du^{1

2}, Ming Yi^{1

2}, Lingyun Feng^{1

2}, Qianwen Peng⁴, Zhihui Cui⁴, Ru Gao⁴, Heping Wang⁴, Yi Huang^{1

2}, Zhi Liu³, Chenhui Wang^{1

2}

Affiliations

¹ The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
² Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
³ Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁴ Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Common variants of the T-cell activation Rho GTPase-activating protein (TAGAP) are associated with the susceptibility to human inflammatory bowel diseases (IBDs); however, the underlying mechanisms are still unknown. Here, we show that TAGAP deficiency or TAGAP expression downregulation caused by TAGAP gene polymorphism leads to decreased production of antimicrobial peptides (AMPs), such as reg3g, which subsequently causes dysregulation of the gut microbiota, which includes Akkermansia muciniphila and Bacteroides acidifaciens strains. These two strains can polarize T helper cell differentiation in the gut, and aggravate systemic disease associated with the dextran sodium sulfate-induced (DSS) disease's phenotype in mice. More importantly, we demonstrated that recombinant reg3g protein or anti-p40 monoclonal antibody exerted therapeutic effects for the treatment of DSS-induced colitis in wild-type and TAGAP-deficient mice, suggesting that they are potential medicines for human IBD treatment, and they may also have a therapeutic effect for the patients who carry the common variant of TAGAP rs212388.

Keywords: Akkermansia muciniphila; Bacteroides acidifaciens; TAGAP; Th17; colitis.