非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）是全球最常见的慢性肝炎，与肝硬化和肝细胞癌密切相关。纠正肠道菌群紊乱虽可改善NASH，但确切机制不明。课题组发现，益生菌的代谢产物短链脂肪酸（short-chain fatty acids，SCFA）负相调节宿主免疫反应，在维持肝脏免疫耐受微环境中可能具有关键作用。为此，本课题拟移植肠道产SCFA菌株和（或）外源补充SCFA干预NASH模型小鼠，通过激动Gi/Gq蛋白偶联受体41（Gi/Gq protein coupled receptor 41, GPR41）/GPR43/GPR109a和选择性失活组蛋白去乙酰化酶，纠正T淋巴细胞亚群失衡，抑制肝脏实质和间质细胞的免疫细胞招募和激活功能，从而借助SCFA介导的“菌群-宿主对话”机制，重建肝脏免疫耐受表型，为NASH的治疗提供新策略。

Nonalcoholic steatohepatitis (NASH) is the most common chronic hepatitis in the world, with close association to liver cirrhosis and hepatocellular carcinoma. Correction of intestinal microflora disorder might be a choice for treatment of NASH, however, the underlying mechanisms still remain unclear. As one of metabolites of probiotics, short-chain fatty acids (SCFA) have been suggested to exert negative effects on the immune response and play critical role in the immune tolerance of normal liver. We thus plan to prevent and treat NASH by transplantation of SCFA-producing microbiota and/or supplement of SCFA in high-fat diet fed mice, and to explore the normalization of regulatory T cell/T helper and their maturation, and prohibit hepatic parachymal/mesenchymal cells induced immune recruitment and activation, through the activation of Gi/Gq protein coupled receptor 41 (GPR41)/GPR43/GPR109a or selective inhibition of histone deacetylase. Finally, hepatic immune tolerance is reconstructed by means of SCFA-mediated ‘microbiota-host crosstalk’ in NASH mice. These findings may provide potential new treatment options for NASH.