甲基吡嗪四甲基物通过调节肠道微生物群失调并恢复肠道屏障完整性，改善与代谢功能障碍相关的脂肪肝炎症。

Abstract

Background and Purpose This study investigated the therapeutic effects and gut–liver axis-related mechanisms of tetramethylpyrazine (TMP) in metabolic dysfunction–associated steatohepatitis (MASH). Experimental Approach Male C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 6 weeks to establish MASH. TMP or pioglitazone was administered during the final 3 weeks. Hepatic injury, intestinal barrier integrity, gut microbiota, bile acids (BAs), short-chain fatty acids (SCFAs) and faecal metabolomics were assessed using histology, biochemical assays, RT-qPCR, western blotting, 16S rDNA sequencing and metabolomics. Faecal microbiota transplantation (FMT) and lipopolysaccharide (LPS)–stimulated Caco-2 cells were used to evaluate microbiota-dependent and direct intestinal protective effects of TMP. Key Results TMP alleviated hepatic steatosis, inflammation and fibrosis in MCD-fed mice. TMP decreased hepatic macrophage infiltration and inflammatory cytokines, including TNF-α, IL-1β and IL-6. In the intestine, TMP restored epithelial structure, increased faecal sIgA, reduced serum LPS, D-lactate, zonulin and TNF-α and up-regulated Claudin-1, ZO-1 and Occludin. TMP improved gut microbial diversity, suppressed proinflammatory bacteria and enriched beneficial taxa. FMT from TMP-treated donors partially reproduced the hepatoprotective effects in recipient mice. TMP further restored BA and SCFA homeostasis, regulated the FXR/FGF15/CYP7A1 axis and remodelled faecal metabolic profiles associated with lipid peroxidation and inflammation. In Caco-2 cells, TMP attenuated LPS-induced IL-1β and IL-6 expression and restored Occludin expression. Conclusion and Implications TMP exerts protective effects against MCD diet–induced MASH by improving hepatic pathology and restoring gut–liver axis homeostasis, including intestinal barrier integrity, gut microbiota composition, BA and SCFA metabolism and faecal metabolic balance. Graphical