GABA调控仔猪肠道SIgA分泌的机制

The low intestinal immunity in piglets promotes various diseases, like infectious diarrhea; thus, the promotion of intestinal SIgA secretion by nutritional strategies can effectively decrease the intestinal infection and diarrhea. My group has found that gamma-aminobutyric acid (GABA) promotes the secretion of intestinal SIgA in the previous investigation; however, the underlying mechanisms by which GABA promotes the SIgA secretion remain to know. This project is conducted to address this issue: 1) by studying the regulation of GABA on the differentiation of IgA+ B cells in vitro model of IgA+ B cell differentiation after activation or inhibition of GABA with metabolomics, transcriptomics, etc. 2) by exploring the influence of GABA on the secretion of intestinal SIgA and intestinal microbiota in model of weaned piglets after supplementation of GABA with metabolomics, microbiome, etc. 3) by investigating the roles of intestinal microbiota on the promotion of GABA in intestinal SIgA secretion in model of germ-free piglets with bacterial colonization, metabolite supplementation, etc. 4) by validating the roles of SIgA on the preventive role of GABA in piglet enterotoxigenic Escherichia coli(ETEC) infection in model of ETEC-infected piglets. The aim is to provide further understanding about the underlying mechanisms by which GABA promotes intestinal mucosal immunity in piglets, and provide experimental evidence for the usage of functional amino acids (e.g., GABA) in piglets to enhance intestinal immunity, and to reduce intestinal infection.

仔猪肠道免疫力低，易发生感染性腹泻等疾病；通过营养措施提高仔猪肠道SIgA分泌能有效预防肠道感染、减少腹泻。本课题组前期发现：γ-氨基丁酸（GABA）能促进肠道SIgA的分泌，但其作用机制未知。本项目首先利用仔猪IgA+B细胞体外分化模型，通过激活或抑制GABA信号，采用转录组学、代谢组学等技术研究GABA对IgA+B细胞分化的调控；然后在断奶仔猪日粮中添加GABA，采用微生物组学、代谢组学等技术研究GABA对肠道微生物和肠道SIgA分泌的影响；在此基础上，利用无菌仔猪模型，通过差异菌定植、差异代谢物添加等方法研究肠道微生物介导GABA促进SIgA分泌的机制；最后采用仔猪肠道感染（ETEC）模型，探讨GABA能否促进SIgA分泌、预防ETEC感染。研究结果不仅能深入阐明GABA对仔猪肠道免疫的调控作用，而且为利用GABA等功能性氨基酸调控仔猪肠道免疫功能、预防病原体感染提供理论依据。

我国每年因各种疾病而死淘生猪占养猪总数的8-10%，其中80%以上为断奶仔猪。引起仔猪高死淘率的原因十分复杂，肠道疾病是重要原因之一。由于断奶仔猪免疫系统发育尚不健全，尤其是肠道黏膜免疫系统对外源病原体识别和抵抗能力弱，容易引发腹泻等疾病导致死亡。因此，通过营养手段提高仔猪肠道黏膜免疫功能，是预防仔猪肠道感染、提高仔猪存活率的关键。基于以上背景，本项目聚焦以下两个科学问题：GABA 如何调控断奶仔猪肠道SIgA的分泌以及ETEC的感染？GABA 调控 IgA+ B 细胞分化的机制是什么？为解决以上科学问题，本项目的研究内容包括以下三个研究方面：（1）GABA调控断奶仔猪肠道SIgA分泌的体内研究；（2）GABA促进IgA+ B细胞分化的机制研究；（3）GABA 调控断奶仔猪ETEC感染的体内研究。最终，本项目揭示了GABA调控IgA+ B细胞分化的内在机制；阐明了肠道微生物介导GABA促进SIgA分泌中的关键作用；鉴定了营养干预肠道免疫功能的新靶点，为利用GABA等功能性氨基酸调控仔猪肠道免疫功能、从而预防病原体感染，特别是禁抗后仔猪肠道感染的预防提供新的营养策略。