Mechanisms of ion channel modulation in human enteroendocrine cells by bacterial metabolites

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Nutrients from the food we eat can provide fuel for cells in our body as well as bacteria that reside in our gut. In a healthy organism, these gut bacteria live in harmony with cells lining the gastrointestinal tract, by producing metabolites that can communicate and regulate the function of these cells in our bodies. We can measure the bacterial metabolites produced, such as short-chain fatty acids (SCFAs) which are produced at high concentrations during fermentation of dietary fibre and secondary bile acids which are produced by bacterial metabolism of bile acids that the body releases to aid in the digestion of fats. However, the mechanism by which these bacterial metabolites affect gastrointestinal cells is still not clear. These signalling pathways are important to uncover as they reveal the fundamental processes governing how cells in our body operate and advances our understanding of the relationship between gut bacteria and humans. We propose to investigate the specifics of these signalling pathways activated by bacterial metabolites, in particular in human enteroendocrine cells (EEC), as these cells are located in close proximity to the production sites of bacterial metabolites and can themselves signal a broad range actions that influence human health. Our research program aims to examine how bacterial metabolites influence ion channel proteins in human EECs. Ion channels dictate the activity of EECs, both the level of electrical excitability and secretion of transmitters, and are subject to influence by signalling molecules. We will use human-derived EECs to study these mechanisms and apply cutting-edge gene-editing approaches to interrogate these signalling pathways. Preliminary results indicate bacterial metabolites, both SCFAs and secondary bile acids, can alter ion channel activity and therefore affect EEC function. Our research will provide new insights into the key pathways gut bacteria activate in local gastrointestinal cells. Understanding exactly how gut bacteria influences their human host is one of the most prominent and contemporary mysteries in science today. This program will advance our understanding of this relationship and produce new research tools to expand this field of study. This program will benefit Canada by providing multidisciplinary training to diverse individuals, which will secure future careers and innovations in the natural sciences.