丁酸盐通过肠上皮组蛋白去乙酰化酶HDAC8调控新生儿坏死性小肠结肠炎Th17/Treg分化平衡的作用机制研究

新生儿坏死性小肠结肠炎（NEC）与免疫稳态失衡密切相关，Th17/Treg分化异常是NEC免疫稳态失衡的重要表现，但其诱导因素与调节机制尚不明确。我们前期发现NEC患儿和小鼠肠道中菌群代谢产物丁酸盐减少，补充丁酸盐能明显改善NEC小鼠Th17/Treg平衡并减轻肠道损伤。机制探索提示丁酸盐可能通过组蛋白去乙酰化酶HDAC8调节肠道上皮细胞分泌炎性因子介导上皮与免疫细胞间通讯，因此本项目将以寻找Th17/Treg分化失衡机制为切入点阐明由于丁酸盐异常引发NEC的致病机制。我们将揭示丁酸盐通过抑制肠道上皮细胞HDAC8对Th17/Treg平衡的调控作用，并解析HDAC8调节H3K14去乙酰化影响Nrf2转录从而刺激肠上皮分泌IL-1β、IL-6导致Th17/Treg失衡的具体机制。本项目有望从菌群代谢产物调节表观遗传角度阐明NEC中Th17/Treg失衡的机制，为临床防治提供理论依据和新思路。

Neonatal necrotizing enterocolitis (NEC) is closely related to immune homeostasis. Abnormal Th17/Treg differentiation is an important manifestation of NEC immune homeostasis, but its inducing factors and regulatory mechanisms are not yet clear. We found that the metabolites named butyrate significantly decreased in the intestine of children and mice with NEC. Butyrate supplementation can significantly improve Th17/Treg balance and reduce intestinal damage in mice with NEC. The mechanism study suggests that butyrate may affect the balance of Th17/Treg by regulating the secretion of inflammatory factors in intestinal epithelial cells through histone deacetylase 8 (HDAC8). Therefore, this project will further explore the mechanism of Th17/Treg differentiation imbalance affected by butyrate in NEC. We will firstly reveal that butyrate regulates the balance of Th17/Treg through inhibiting HDAC8 located in intestinal epithelial cells. And then show how HDAC8 controls the intestinal epithelial cells secreting IL-1β、IL-6 and lastly affects the balance of Th17/Treg. This project is expected to clarify the mechanism of Th17/Treg imbalance in NEC from the perspective of epigenetic regulation by bacterial flora metabolites, and provide new ideas for clinical prevention and treatment.