基于SCFAs对Th17/Treg平衡的影响探讨一种特殊多纤维复合物对克罗恩病的干预机制

Imbalance of Th17/Treg plays a key role in the pathogenesis of Crohn’s disease (CD). In addition, the intestinal bacterial diversity and metabolites play an essential role in maintaining the Th17/Treg balance. Short chain fatty acids (SCFAs) are the dominating end products of bacterial fermentation of non-digestible polysaccharides by intrinsic intestinal digestive enzymes in the large bowel, and are generated by commensal bacteria, which have an important effect on colonic homeostasis maintenance, epithelial integrity and immune cell function, migration and apoptosis. Our previous study demonstrated that prebiotic multifibre mixture (MF) ameliorates colitis, decreased epithelial cells apotosis, by regulating imunologic function. Based on our preliminary results, we proposed a study performing in vivo and in vitro, which will focus on the role of gut bacterial diversity and SCFAs on Th17/Treg and intestinal barrier function in CD mouse models, and further explore the potential mechanisms of the effects of metabolites of MF on colitis. The results of our study would provide evidence to the understanding of the pathogenesis of CD, and may also shed light on the clinical management for CD.

Th17/Treg失衡在克罗恩病（Crohn’s disease, CD）发病机制中起核心角色。肠道菌群的数量、多样性和代谢产物在维持肠黏膜Th17/Treg平衡中起重要作用。肠道菌群能够对非消化吸收性多糖进行代谢酵解，产生的短链脂肪酸（short-chain fatty acids，SCFAs）具有促进肠黏膜增生，维护肠黏膜形态，参与免疫细胞功能维护等。本课题组前期研究发现采用纤维含量与健康人饮食相符合的一种特殊多种纤维复合物（prebiotic multifibre mixture, MF）组成的非消化吸收性多糖能够有效治疗免疫介导的CD模型（IL-10-/-）小鼠结肠炎，改善黏膜免疫功能，减少肠上皮细胞凋亡。在此研究基础上，本课题以CD模型小鼠为研究对象，采用体内外研究相结合，探讨MF治疗后肠道菌群变化及代谢产物SCFAs对Th17/Treg平衡和肠黏膜屏障功能的影响及其机制。

炎症性肠病（Inflammatory bowel disease，IBD）包括溃疡性结肠炎（ulcerative colitis）和克罗恩病（Crohn’s disease，CD），是一种非特异性炎症性肠病，近年来的发病率呈逐年上升趋势，给社会生产力和个人生活质量带来极大影响，引起各界高度重视。尽管这些年来对IBD进行了深入的研究，但是IBD的发病机制尚不清楚。目前主要通过化学诱导、转基因和基因敲除小鼠模型来研究IBD的分子学机制。虽然IBD模型小鼠不能完全代表人类疾病，但是IL-10敲除小鼠的肠道病理学改变与人类CD极为相似。在在特定的无菌条件下（Under specific pathogen-free conditions，SPF）环境下，会产生类似CD的自发性结肠炎，表现为黏膜固有层大量的淋巴细胞和巨噬细胞浸润。人类肠道寄居着约大量的微生物群，其中梭状芽胞杆菌属对非消化吸收性纤维进行酵解，产生约50-100mM的短链脂肪酸（short-chain fatty acids，SCFAs）。目前的研究表明，与健康人相比，IBD患者的粪便中SCFAs含量明显降低，且其含量越低，肠道炎症越重。.本研究中旨在探讨MF治疗CD中的相关机制。我们采用IL-10−/−小鼠作为CD疾病模型，予以MF喂养处理，观察MF对CD模型小鼠肠黏膜屏障及黏膜免疫的影响及干预机制。证明了应用MF产生SCFA，改善黏膜屏障损伤，诱导结肠黏膜固有层CD4+CD25+Foxp3+ Tregs的分化和M2巨噬细胞极化，有效改善结肠炎症状，为今后在临床应用MF治疗治疗CD提供理论依据。