肠道菌群-SCFAs谱-Tregs细胞轴在婴幼儿食物过敏中作用及分子机制研究

Food allergy (FA) is one of the common diseases in infants and young children, however, its pathogenesis is still unclear. Previous studies have found that infancy is the critical time-windows for the establishment of gut microbiota, which plays a vital role in host intestinal mucosal immune regulation. Our study has shown that the alterations of gut microbiota in infants are associated with FA tightly. The short-chain fatty acids (SCFAs), which derive from microbial metabolism in the gut, emerge as major mediators in linking gut microbiota and immune system. Allergen-specific regulatory T cells (Tregs) play a central role in inducing oral tolerance, which is regulated by gut microbiota. We speculate that SCFAs may be involved in the regulation of FA, which can mediate the induction and regulation of Tregs. Our present project carries out the integrated study of gut microbiota-SCFAs-Tregs axis interaction, with the focus shifting into host-gut microbiota cross-talk. Our study will investigate the dynamic changes of gut microbiota and SCFAs profiles in the critical stages of FA, and screen out the key functional bacteria and key bacterial metabolites that are associated with FA. In addition, we also try to investigate the effect of key functional bacteria and key bacterial metabolites on Tregs, which will influence the sensitization of food allergens. From human beings, animals, cells and molecular levels, we try to clarify the role of gut microbiota and its metabolites SCFAs on the development of FA by regulating intestinal Treg cells in vivo or in vitro. In addition, given the large potential of microbial metabolites as modulators of the immune response, it will pose a major challenge for future research to develop dietary interventions for FA. Targeted inference with microbiota metabolite production and downstream immunomodulation presents a very attractive and non-invasive avenue for future therapy design.

食物过敏(FA)是婴幼儿的常见病多发病但其发病机制不明。本课题组前期研究发现婴幼儿FA与肠道菌群改变密切相关，而其关键代谢产物短链脂肪酸(SCFAs)可介导菌群与免疫系统的沟通。肠道调节性T细胞(Tregs)是诱导肠道免疫耐受的关键，其受肠道菌群的调控。我们推断SCFAs可能通过诱导调控Tregs介导肠道菌群对FA精细调控。为验证上述假说，本项目拟开展的肠道菌群-SCFAs谱-Tregs轴交互作用的整合性研究，解析肠道菌群和SCFAs在FA发生关键阶段的动力学变化规律，筛选FA相关关键功能菌和关键代谢产物，探明其诱导调控Tregs对食物过敏原致敏的影响，从人体、动物、细胞、分子水平揭示肠道菌群及SCFAs诱导调控Tregs在婴幼儿FA发生发展的作用和分子机制，明确SCFAs作为免疫应答调节剂的巨大应用潜力，为开发基于肠道菌群为靶点的FA膳食调控策略提供理论依据和实验基础。

食物过敏(food allergy, FA)是婴幼儿的常见病多发病但其发病机制不明。本课题组前期研究发现婴幼儿FA与肠道菌群改变密切相关，而肠道菌群关键功能代谢产物短链脂肪酸(SCFAs)是肠道菌群功能的直接执行者，可介导菌群与免疫系统的沟通。肠道调节性T细胞(Tregs)是诱导肠道免疫耐受的关键，其受肠道菌群的调控。本项目针对肠道菌群-FA-免疫功能调控“三位一体”网络互作中亟需解决的科学难题，聚焦肠道菌群-SCFAs-Treg轴交互作用的整合性研究。研究发现，不同年龄组FA患儿肠道菌群及系统性炎症呈现出动态变化。IgE介导的与非IgE介导的食物过敏患儿肠道菌群结构和组成显著差异，其中牛奶过敏患儿病情缓解和儿童早期肠道菌群改变与牛奶特异性IgE状态密切。研究发现，肠道菌群中产SCFAs的菌显著减少，尤其是产丁酸关键功能菌，而粪便菌群代谢组学也明确发现食物过敏患儿SCFAs谱出现了显著的改变，乙酸水平显著升高，丁酸、异丁酸、戊酸、异戊酸的水平显著降低。为进一步明确不同产SCFAs的关键功能菌在肠道黏膜免疫调控中的作用和机制，本研究进而采用单细胞测序技术，采用不同的益生菌株对无菌大鼠进行干预，研究发现，产丁酸酪酸梭菌与产乳酸婴儿双歧杆菌对大鼠肠道黏膜免疫调控作用具有显著差异，主要体现在T细胞诱导调控差异方面，这也进一步说明肠道黏膜Tregs调控是食物过敏和口服免疫耐受结局的关键。进而本项目结合本研究，开展了临床疾病肠道菌群及其代谢产物SCFAs的研究，发现产丁酸菌减少，产乳酸菌增多，并与宿主免疫紊乱密切相关，再次证实产SCFAs益生菌在疾病治疗中的关键性作用。这为后续开展以肠道菌群为靶点的疾病防治奠定基础，进一步实现疾病防治关口前移，具有重要的科学意义和临床价值。