肠道菌群代谢产物短链脂肪酸对炎症性肠病Th1和Th17细胞的免疫调节效应研究

Inflammatory bowel diseases are a group of chronic nonspecific intestinal disorders. Although the exact etiology of IBD is still not completely understood, it appears to be disorders of the host immune response to luminal microbiota. Of particular interest are short-chain fatty acids (SCFA), which are solely metabolized by gut bacteria. It has been shown that SCFAs not only participate in the regulation of innate immune responses, such as stimulating the migration of neutrophils and enhancing the phagocytosis of macrophages, but also in the adaptive responses by facilitating naïve T-cells differentiation into FoxP3+ regulatory T-cells and promoting the secretion of IgA by B cells. Meanwhile, the specific sensing receptor, GPR43, is still associated with the immune regulation. Our preliminary data showed that SCFAs influenced the function of Th1 and Th17 cells through GPR43 pathway, but the mechanisms involved are still unclear. Furthermore, the central hypothesis of this project is that SCFA promotes Th1 and Th17 cell differentiation and production of cytokines in a GPR43-dependent manner, which leads to preservation of intestinal immune homeostasis and inhibition of IBD. This work will provide an important theoretical basis for IBD immune therapy.

炎症性肠病(IBD)是一组慢性肠道非特异性炎性疾病，目前其病因和发病机制尚未明确。肠道菌群参与了IBD的病理生理发展，它的代谢产物短链脂肪酸也引起了许多学者的关注。目前已有研究表明，短链脂肪酸不仅参与调节体内固有性免疫应答，诱导中性粒细胞迁移、增强巨噬细胞吞噬功能；还参与调节适应性免疫应答，促进Treg细胞分化、诱导B细胞分泌IgA，加强宿主肠道黏膜中抗体反应。同时，它的特异性G蛋白偶联受体GPR43也与肠道炎症和免疫调节密切相关。我们前期研究发现，短链脂肪酸可通过活化GPR43通路影响Th1/Th17细胞功能，但其具体机制尚不清楚。由此，我们提出本课题的研究假说，短链脂肪酸可通过GPR43通路调节Th1/Th17细胞功能，影响其细胞分化及细胞因子的分泌，进一步参与肠道免疫调节，抑制肠道炎症发生。该研究将为临床上IBD的治疗提供新的理论基础和分子靶点，为患者解除病痛。

炎症性肠病(inflammatory bowel disease，IBD)是一组慢性肠道非特异性炎性疾病，主要包括溃疡性结肠炎(ulcerative colitis，UC)和克罗恩病(Crohn’s disease，CD)，发病部位常常可累及整个消化道黏膜。肠黏膜固有性和获得性免疫应答共同参与了IBD的病理生理发生过程。人体胃肠道是一个开放的生态系统，肠道炎症需要体内共生菌的参与和调节，肠道共生菌直接影响着机体生理和代谢变化。肠黏膜免疫系统除了能识别病原微生物表面的病原体相关分子模式以外，还可通过识别肠道微生物代谢产物，进一步发挥生物学效应。其中，短链脂肪酸作为肠道微生物代谢的主要产物引起了广泛的关注。本项目证实短链脂肪酸尤其是丁酸可通过GPR43通路调节Th1细胞功能，并且该作用主要通过STAT3、mTOR通路调节Blimp1表达，进一步影响Th1细胞分泌IL-10，参与肠道免疫调节，抑制肠道炎症发生。该研究将为临床上IBD的治疗提供新的理论基础和分子靶点，为患者解除病痛。