Mechanisms of alteration of gastrointestinal physiology by gut microbes

摘要 我们实验室研究的总体目标是 确定肠道 微生物群及其产物改变胃肠道（GI）腔生理学， 发展 基于微生物群的治疗操作，以纠正疾病中的生理改变， 肠易激综合征（IBS）与肠道微生物群的改变有关。我们的K 08资助 对肠道微生物群产品影响GI生理学的机制的研究发现， 细菌衍生代谢物色胺的作用。从我目前的K 08数据显示， 在健康人的肠道中发现的活泼瘤胃球菌和生孢梭菌， 携带色氨酸脱羧酶，可将食物中的色氨酸转化为色胺。 此外，我们的初步研究表明，色胺增加短路电流 （代表离子通量;分泌的替代物）在体外穿过Ussing中的结肠上皮 该效应可被5-羟色胺（5-HT）受体4拮抗剂抑制。我们 总的目的是确定色胺对肠分泌的影响。我们建议 确定假设1中外源性色胺在调节肠分泌中的作用， 细菌衍生色胺在假说2中的作用以及 色胺假说3。这些实验虽然与以前的工作有着基础性的联系， 与K 08相关的工作的新的但合乎逻辑的扩展，可以在 确定奖励期限。这项研究的结果可能有助于开发 能够产生感兴趣的代谢物以纠正改变的代谢物的新的工程化益生菌， 肠易激综合征等疾病的生理学基础。

ABSTRACT The overall goal of our laboratory's research is to determine the mechanisms by which gut microbiota and their products alter gastrointestinal (GI) tract luminal physiology and to develop microbiota-based therapeutic manipulations to correct altered physiology in diseases like Irritable Bowel Syndrome (IBS) associated with alterations in gut microbiota. Our K08 funded research into mechanisms by which gut microbiota products affect GI physiology identified a role for the bacteria-derived metabolite tryptamine.Data from my current K08 show that Ruminococcus gnavus and Clostridium sporogenes, found in the gut of healthy individuals, carry the enzyme tryptophan decarboxylase which can convert dietary tryptophan to tryptamine. Furthermore our preliminary studies show that tryptamine increases short circuit current (representing ionic flux; surrogate for secretion) across the colonic epithelium in vitro in Ussing chamber studies and this effect can be inhibited by serotonin (5-HT) receptor 4 antagonists. Our overall aim is to determine the effect of tryptamine, on intestinal secretion. We propose to determine the role of exogenous tryptamine in regulation of intestinal secretion in hypothesis 1, the role of bacterial-derived tryptamine in hypothesis 2 and the mechanism of action of tryptamine in hypothesis 3. These experiments, while foundationally linked to previous work, are a new but logical extension of the work associated with the K08 and can be completed in the defined award period. The results from this study will potentially contribute to development of novel engineered probiotics capable of producing a metabolite of interest to correct the altered physiology in diseases like IBS.