Akkermansia muciniphila inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated?dT17 cell and macrophage polarization

Current evidence indicates that the next-generation probiotic Akkermansia muciniphila (A. muciniphila) has therapeutic potential for nonalcoholic fatty liver disease (NAFLD), especially its inflammatory stage known as nonalcoholic steatohepatitis (NASH). However, the mechanisms of A. muciniphila in NASH prevention remain unknown. Here, A. muciniphila supplementation prevented hepatic inflammation in high-fat diet-induced NASH mice, characterized by reduced hepatic proinflammatory macrophages (M1) and ?dT and ?dT17 cells. Consistently, hepatic M1 and ?dT cells were enriched in biopsy-proven NASH patients and high-fat/high-carbohydrate diet-induced NASH mice. Antibiotics reduced hepatic M1, ?dT and ?dT17 cells in NASH mice. Furthermore, A. muciniphila inhibited intestinal barrier disruption and accordingly downregulated hepatic Toll-like receptor 2 (TLR2) expression in NASH mice. The activation of TLR2 by lipoteichoic acid enriched hepatic ?dT17 cells (not M1) in normal diet-fed mice and neutralized the ?dT cell-lowering and liver inflammation-protecting effects of A. muciniphila in NASH mice. Additionally, activated ?dT cells could promote macrophage polarization via IL-17. Our study first supported that A. muciniphila prevented NASH by modulating TLR2-activated ?dT17 cells and further macrophage polarization, facilitating clinical therapeutic applications.