短链脂肪酸介导“菌群-宿主对话”恢复肝脏免疫耐受状态治疗非酒精性脂肪性肝炎

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.

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。

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，本课题移植肠道产SCFA菌株和(或)外源补充SCFA干预NASH模型小鼠，完成了肠道探讨以丁酸钠（sodium butyrate，NaB）为代表的短链脂肪酸恢复肝脏免疫耐受状态对NAFLD的防治作用。主要探索并证实了以肠道菌群为靶向的干预包括粪菌移植、CB 益生菌及NaB主要或部分通过改善HFD引起的小鼠肠道菌群紊乱，纠正HFD引发的炎症与免疫微环境失衡，增强肠道粘膜屏障，研究中发现NaB可能通过增加LKB1磷酸化和AMP/ATP比值，促进AMPK活化等途径，发挥肝细胞保护作用。此外，NaB通过增加AMPK和insig的交互作用，减少insig泛素化降解，进而抑制SREBP-1c转录活性;同时NaB激活的AMPK也可抑制SREBP-1c剪切。提示NaB具有抑制肝细胞脂质从头合成的作用。除NaB外，亦探索了氧化三甲胺(trimethylamine N-oxide，TMAO)和吲哚丙酸(Indole propionic acid，IPA)等肠道菌群代谢产物在NAFLD的疾病过程中的作用。发现肠道菌群代谢产物TMAO 降低大鼠肝脏胆固醇超载减轻高脂高胆固醇饮食诱导的NASH。IPA可能通过其减少内毒素血症，改善肠道菌群失调缓解高脂饮食诱导的NASH表型。费格森埃希菌通过分泌msRNA 23487促进了非肥胖大鼠脂肪性肝炎和纤维化的发病机制。该课题进一步探讨了益生菌在恢复肝脏免疫耐受状态中发挥的防治作用,通过非靶代谢组检测发现益生菌治疗影响非酒精性脂肪性肝炎小鼠的肠道-肝脏-骨骼肌代谢轴，主要富集在三羧酸循环、磷脂代谢、胆汁酸代谢和氨基酸代谢通路，共同影响非酒精性脂肪性肝炎小鼠肝脏表型,通过益生菌的治疗可以恢复肠道菌群的物种丰富度和分布均匀程度。该课题聚焦了肠道菌群代谢产物干预NASH的“菌群-宿主对话”机制，为NASH的治疗提供新策略。