Regulation of colonic epithelial barrier function through short chain fatty acid signaling

我的研究计划的长期目标是充分了解微生物-宿主肠道沟通的机制作用(S)，其中微生物衍生的代谢物(来自饮食前体)可以影响结肠上皮屏障(EB)的完整性和基本功能，如防御(粘液屏障和抗微生物蛋白)和受损EB结构的修复。该计划解决的知识鸿沟旨在研究微生物代谢物如何调节EB的完整性和功能，包括EB防御和修复的基本生理过程。本文提出的研究计划是我之前工作的合理扩展，将重点放在短链脂肪酸(SCFA)上，短链脂肪酸是由膳食中不可消化的碳水化合物前体(例如膳食中的可溶性纤维)产生的主要微生物代谢物。短期目标将通过一系列原代完整的结肠器官培养和啮齿动物实验来实现，这些实验旨在利用体外/体外(目标1和2)和体内(目标3)模型，确定单个SCFA(单独或联合在生理相关水平上)影响结肠EB完整性(顶端连接复合体成分和功能性EB通透性测试)和功能(包括上皮细胞细胞动力学、粘液和抗微生物蛋白防御以及损伤修复)的信号机制。本项目中使用的实验方法将作为未来评估其他微生物代谢物影响宿主结肠EB功能的机制的模型系统，然而，最初的重点是SCFA。该计划的成果将首先促进关于微生物衍生代谢物对基本基本胃肠功能的影响的基本知识，包括EB的完整性、功能和修复，其次将通过了解增加SCFA膳食前体摄入量的下游分支向农业食品部门和食品政策机构提供信息。该项目将支持16名HQP(1名博士，2名硕士(论文)，8名硕士(非论文)，5名本科生)的培训。

The long-term objective of my research program is to fully understand the mechanistic role(s) of microbial-host intestinal communication, wherein microbial-derived metabolites (from dietary precursors) can influence colonic epithelial barrier (EB) integrity and essential functions such as defense (mucus barrier and anti-microbial proteins) and repair of damaged EB structure. The knowledge gap addressed by this program aims to study how microbial metabolites regulate EB integrity and function, including the fundamental physiological processes of EB defense and repair. The research program proposed herein is a logical extension of my previous work, and will focus on short chain fatty acids (SCFA), the predominant microbial metabolites produced from dietary non-digestible carbohydrate precursors (e.g. dietary soluble fibres). The short-term objectives will be achieved through a series of primary intact colon organoid culture and rodent experiments designed to determine the signaling mechanisms through which individual SCFA (alone or in combination at physiologically relevant levels) affect colonic EB integrity (apical junctional complex components and functional EB permeability tests) and functions (including epithelial cell cytokinetics, mucus and anti-microbial protein defenses and repair from damage) using in vitro/ex vivo (Objectives 1&2) and in vivo (Objective 3) models. The experimental approach utilized in this program will serve as a model system for future assessment of mechanisms through which other microbial metabolites influence host colonic EB function, however, the initial focus is on SCFA. Outcomes from this program will first advance basic knowledge of the effect of microbial-derived metabolites on essential basic gastrointestinal functions including EB integrity, function and repair, and secondly, will provide information to the Agri-Food sector and food policy agencies by understanding the downstream ramifications of increasing intake of SCFA dietary precursors. The program will support the training of 16 HQP (1 PhD, 2 MSc (thesis), 8 MSc (non-thesis), 5 undergraduates).