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

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 (Ticam1ΔIEC) mice and the control (Ticam1fl/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 Ticam1ΔIEC mice, which had improved MASH disorders compared with Ticam1fl/fl. Additionally, HFD-fed Ticam1ΔIEC 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-Ticam1ΔIEC 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.