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

细菌代谢物调节人肠内分泌细胞离子通道的机制

• 批准号: RGPIN-2022-04187
• 负责人: Lu, Van
• 金额: $ 2.04万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763346
• 关键词: Mechanisms; ion; channel; modulation; human

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.

我们吃的食物中的营养素可以为我们体内的细胞以及肠道中的细菌提供燃料。在健康的生物体中，这些肠道细菌与胃肠道细胞和谐相处，通过产生代谢物来沟通和调节我们体内这些细胞的功能。我们可以测量产生的细菌代谢物，例如短链脂肪酸（SCFA），它在膳食纤维发酵过程中以高浓度产生，以及二级胆汁酸，它是由身体释放的胆汁酸的细菌代谢产生的，以帮助消化脂肪。然而，这些细菌代谢物影响胃肠道细胞的机制仍不清楚。这些信号通路非常重要，因为它们揭示了控制我们体内细胞如何运作的基本过程，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具体情况，特别是在人类肠内分泌细胞（EEC）中，因为这些细胞位于细菌代谢物的生产场所附近，并且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内皮细胞中的离子通道蛋白。离子通道决定了EEC的活性，包括电兴奋性和递质分泌水平，并受到信号分子的影响。我们将使用人源性EEC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，细菌代谢产物，SCFA和次级胆汁酸，可以改变离子通道的活性，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最现代的谜团之一。该计划将促进我们对这种关系的理解，并产生新的研究工具来扩大这一研究领域。该计划将通过为不同的个人提供多学科培训使加拿大受益，这将确保自然科学领域的未来职业和创新。