Mechanisms of alteration of gastrointestinal physiology by gut microbes

肠道微生物改变胃肠生理学的机制

• 批准号: 9226118
• 负责人: Purna C Kashyap
• 金额: $ 7.95万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226118
• 关键词: Address; Affect; Animal Model; Aromatic-L-Amino-Acid Decarboxylases; Award; Bacteria; Carboxy-Lyases; Clostridium; Colon; Complex; Data; Decarboxylation; Development; Diet; Dietary Component; Disease; Ecosystem; Electrolytes; Engineering; Enzymes; Epithelial; Epithelium; Fermentation; Fluids and Secretions; Foundations; Functional disorder; Funding; Future; Gastrointestinal Physiology; Gastrointestinal tract structure; Goals; Health; Human; Immune system; In Vitro; Individual; Indoles; Intestinal Secretions; Intestines; Irritable Bowel Syndrome; Laboratory Research; Ligands; Link; Mediating; Mediator of activation protein; Microbe; Molecular; Mucous body substance; Neurotransmitters; Pathway interactions; Physiological; Physiology; Play; Probiotics; Process; Regulation; Research; Role; Ruminococcus; Serotonergic System; Serotonin; Signal Transduction; Symbiosis; Technology; Testing; Therapeutic; Tryptamines; Tryptophan; Work; bacterial metabolism; base; commensal microbes; experimental study; gastrointestinal; gut microbiota; in vivo; interest; member; microbial; microbiota; monoamine; novel; pathogenic bacteria; prevent; programs; receptor; serotonin receptor; tool; vitamin biosynthesis

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.

摘要 我们实验室研究的总体目标是 确定肠道的作用机制 微生物区系及其产物改变胃肠道(GI)腔生理和 发展 基于微生物区系的治疗操作，以纠正疾病中改变的生理 肠易激综合征(IBS)与肠道微生物区系改变相关。我们资助的K08 肠道微生物区系产物影响胃肠道生理的机制研究已确定 细菌衍生的代谢物色胺的作用。来自我目前K08的数据显示 在健康人的肠道中发现的嗜瘤胃球菌和产孢梭菌， 携带色氨酸脱羧酶，这种酶可以将饮食中的色氨酸转化为色胺。 此外，我们的初步研究表明，色胺会增加短路电流 (代表离子通量；替代分泌物)在体外穿过美国的结肠上皮 室内研究发现，5-羟色胺(5-羟色胺)受体4拮抗剂可以抑制这种作用。我们的 总体目标是确定色胺对肠道分泌的影响。我们建议 在假设1中确定外源性色胺在肠道分泌调节中的作用， 细菌衍生色胺在假说2中的作用及其作用机制 假设3中的色胺。这些实验虽然从根本上与以前的工作有关，但 与K08相关的工作的新的但合乎逻辑的扩展，可以在 确定的奖励期限。这项研究的结果将潜在地有助于 新型工程益生菌能够产生感兴趣的代谢物来纠正改变的 IBS等疾病的生理学。