脆弱拟杆菌ATCC25285通过TGF-β/Smad3通路诱导Treg细胞分化缓解结肠炎  

Bacteroides fragilis ATCC25285 relieves colitis by inducing Treg cells differ⁃entiation via the TGF-β/Smad3 signaling pathway

作　　者：魏芳 范梦慧 刘光臣 顾馨月 邢莹莹[1] WEI Fang;FAN Menghui;LIU Guangchen;GU Xinyue;XING Yingying(School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]中国药科大学生命科学与技术学院,南京211198

出　　处：《中国药科大学学报》2023年第2期226-237,共12页Journal of China Pharmaceutical University

基　　金：国家重点研发项目(No.2017YFD0400303);国家自然科学基金资助项目(No.81971562);宁夏回族自治区重点研发计划项目(No.2020BFG02012);江苏省高校优先学术项目开发(PAPD)。

摘　　要：肠道菌群的变化通常与不同的胃肠道疾病有关,维持肠道菌群稳态可以增强免疫耐受性,调节肠道免疫平衡。已有研究发现,增加肠道菌群拟杆菌门中脆弱拟杆菌(B.fragilis)的相对丰度,可以显著增强肠道调节性T细胞(Treg)和抗炎细胞因子的表达,缓解肠道炎症。然而,B.fragilis调节肠道免疫的具体机制尚不清楚。本研究通过给SPF级C57BL/6小鼠饮用3%DSS溶液构建急性结肠炎模型,自由饮用7 d后,通过灌胃对已患结肠炎小鼠外源性补充B.fragilis,研究B.fragilis对肠道免疫的调控作用及其作用机制。实验结果表明,B.fragilis可以改善结肠炎小鼠的肠道菌群紊乱,增加肠道菌群主要代谢产物短链脂肪酸(SCFAs)的含量。通过提取小鼠组织淋巴细胞、初始CD4+T细胞、使用脂质体修饰的siRNA敲低小鼠Smad3,采用流式细胞术进一步研究发现B.fragilis能够通过TGF-β/Smad3信号通路诱导肠道Treg细胞及相关细胞因子的表达,增强肠道调节免疫,进而缓解结肠炎。此外,本研究还发现B.fragilis通过增加肠道中活性氧(ROS)的表达来激活TGF-β,从而诱导Treg细胞分化并发挥免疫调节作用。The changes in intestinal flora are usually associated with different gastrointestinal diseases,and intestinal flora homeostasis can enhance immune tolerance and regulate intestinal immune balance.Previous studies have found that the increase of the relative abundance of Bacteroides fragilis(B.fragilis)in Bacteroides intestinalis can significantly enhance the expression of intestinal regulatory T cells(Treg)and anti-inflammatory cytokines,thus alleviating intestinal inflammation.However,the mechanism of B.fragilis regulating intestinal immunity is still unclear.In this study,an acute colitis model was constructed by giving 3%DSS in drinking water solution to SPF-grade C57BL/6 mice for 7 days,and exogenous supplementation B.fragilis was given to mice by gastric gavage to study its regulatory effect on intestinal immunity and its mechanism of action.The results showed that B.fragilis could improve the intestinal flora disorder in mice with colitis and increase the content of short-chain fatty acids(SCFAs),the main metabolite of the intestinal flora.By extracting mouse tissue lymphocytes,naive CD4+T cells,and liposome-modified siRNA knockdown mouse Smad3,it was further discovered by flow cytometry that B.fragilis induced the expression of intestinal Treg cells and related cytokines through the TGF-β/Smad3 signaling pathway,which enhanced intestinal regulatory immunity and alleviated colitis.It was also found that B.fragilis activated TGF-βby increasing the expression of reactive oxygen species(ROS),thus inducing Treg cell differentiation and playing an immunomodulatory role.

关 键 词：脆弱拟杆菌 胃肠道微生物 调节性T细胞 TGF-β/Smad3 结肠炎 

分 类 号：Q939.91[生物学—微生物学]