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

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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).