Suppression of intestinal Ticam1 ameliorated MASH via Akkermansia muciniphila QAA37749.1 mediated betaine transformation

Zhonglin Li; Wenkang Gao; Hang Yuan; Xiaoli Pan; Ruiqing Yuan; Weijun Wang; Lei Guan; Lilin Hu; Yue Chen; Zilu Cheng; Ruohang He; Lei Zhang; Bowen Yang; Qingjing Zhu; Minglu Liang; Ekihiro Seki; Rong Lin; Huikuan Chu; Ling Yang

doi:10.1016/j.bbadis.2024.167571

Suppression of intestinal Ticam1 ameliorated MASH via Akkermansia muciniphila QAA37749.1 mediated betaine transformation

Biochim Biophys Acta Mol Basis Dis. 2024 Nov 12;1871(1):167571. doi: 10.1016/j.bbadis.2024.167571. Online ahead of print.

Authors

Zhonglin Li¹, Wenkang Gao¹, Hang Yuan¹, Xiaoli Pan¹, Ruiqing Yuan¹, Weijun Wang¹, Lei Guan¹, Lilin Hu¹, Yue Chen¹, Zilu Cheng¹, Ruohang He¹, Lei Zhang¹, Bowen Yang², Qingjing Zhu³, Minglu Liang⁴, Ekihiro Seki⁵, Rong Lin⁶, Huikuan Chu⁷, Ling Yang⁸

Affiliations

¹ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
² Xinjiang Medical University, 567 Shangde North Road, Urumqi, Xinjiang, China.
³ Department of Liver Diseases, Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1 Yintan Road, Wuhan 430000, China.
⁴ Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, 1277 Jiefang Avenue, Wuhan 430022, China; Hubei Clinical Research Center of Metabolic and Cardiovascular Diseases, 1277 Jiefang Avenue, Wuhan 430022, China.
⁵ Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address: linrong@hust.edu.cn.
⁷ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address: 2012XH0827@hust.edu.cn.
⁸ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, 1277 Jiefang Avenue, Wuhan 430022, China; Hubei Clinical Research Center of Metabolic and Cardiovascular Diseases, 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address: yanglinguh@hust.edu.cn.

PMID: 39536991
DOI: 10.1016/j.bbadis.2024.167571

Abstract

Background & aims: Gut inflammation caused by diets could damage the intestinal barrier, which increases the liver exposition to pathogenic substances. Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (Ticam1) is a key molecule in the Toll-like receptors (TLRs) pathway, which is important for the immune defense against pathogens such as bacteria or viruses. In this study, mouse intestinal epithelial cell (IEC) Ticam1 was knocked out to suppress the intestinal inflammation response in metabolic dysfunction-associated steatohepatitis (MASH) to investigate its influence on the development of MASH.

Methods: The IEC-specific Ticam1 knockout (Ticam1^ΔIEC) mice and the control (Ticam1^fl/fl) mice were fed with high-fat high-fructose diet (HFD) for 22 weeks to evaluate the gut alteration and the MASH-associated disorders. The intestinal secreted immunoglobulin A (sIgA) and IgA-secreting immune cells were detected. Shotgun metagenomic sequencing was used to find the gut microbiome shift in different groups. Liquid chromatography mass spectrometry was also performed to evaluate the change of serum metabolites caused by the gut microbiome alteration.

Results: The gut inflammation and gut barrier dysfunction were both alleviated in HFD-fed Ticam1^ΔIEC mice, which had improved MASH disorders compared with Ticam1^fl/fl. Additionally, HFD-fed Ticam1^ΔIEC mice had increased sIgA and intestinal IgA-secreting immune cells. It showed a significantly higher content of Akkermansia muciniphila. We proved that Akkermansia muciniphila encoded a protein named QAA37749.1 that could promote the conversion of choline to betaine, through which the development of MASH was inhibited in HFD-Ticam1^ΔIEC mice.

Conclusion: Deletion of IEC Ticam1 alleviated MASH disorder and gut dysfunction in mice. It enhanced the level of intestinal sIgA and the growth of Akkermansia muciniphila, which supported the betaine transformation by QAA37749.1. Suppressing IEC Ticam1 might be a promising strategy for MASH disorder.

Keywords: Akkermansia muciniphila; Betaine; MASH; Ticam1.