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

我们所吃的食物中的营养物质可以为我们体内的细胞和肠道中的细菌提供能量。在一个健康的生物体中，这些肠道细菌通过产生代谢物与胃肠道细胞和谐相处，代谢物可以沟通和调节这些细胞在我们体内的功能。我们可以测量产生的细菌代谢物，如短链脂肪酸（SCFAs），它是在膳食纤维发酵过程中高浓度产生的，次级胆汁酸是由细菌代谢的胆汁酸产生的，身体释放胆汁酸来帮助脂肪的消化。然而，这些细菌代谢物影响胃肠道细胞的机制尚不清楚。发现这些信号通路很重要，因为它们揭示了控制我们体内细胞运作的基本过程，并促进了我们对肠道细菌与人类之间关系的理解。我们建议研究细菌代谢物激活的这些信号通路的细节，特别是在人类肠内分泌细胞（EEC）中，因为这些细胞靠近细菌代谢物的产生位点，并且它们本身可以发出影响人类健康的广泛行动的信号。我们的研究计划旨在研究细菌代谢物如何影响人类脑脊液中的离子通道蛋白。离子通道决定脑脊液的活性，包括电兴奋性水平和递质的分泌，并受到信号分子的影响。我们将使用人类衍生的EECs来研究这些机制，并应用尖端的基因编辑方法来询问这些信号通路。初步结果表明，细菌代谢物，SCFAs和次级胆汁酸，可以改变离子通道活性，从而影响EEC功能。我们的研究将为肠道细菌在局部胃肠道细胞中激活的关键途径提供新的见解。确切地了解肠道细菌如何影响它们的人类宿主是当今科学中最突出和当代的谜团之一。这个项目将促进我们对这种关系的理解，并产生新的研究工具来扩展这一研究领域。该项目将为不同的个人提供多学科培训，从而使加拿大受益，这将确保未来在自然科学领域的职业和创新。

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.