Mechanisms of alteration of GI physiology by gut microbes

肠道微生物改变胃肠道生理学的机制

• 批准号: 9547844
• 负责人: Purna C Kashyap
• 金额: $ 35.78万
• 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: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9547844
• 关键词: Affect; Aromatic-L-Amino-Acid Decarboxylases; Bacteria; Bicarbonates; Biological Response Modifier Therapy; Clostridium; Complex; Constipation; Data; Decarboxylation; Development; Diet; Disease; Ecosystem; Electrolytes; Engineered Probiotics; Enzymes; Epithelial; Epithelium; Exhibits; Fluids and Secretions; Gastrointestinal Physiology; Gastrointestinal tract structure; Genes; Genetic Engineering; Gnotobiotic; Goals; Health; Human; In Vitro; Intestinal Secretions; Intestines; Irritable Bowel Syndrome; Knockout Mice; Laboratory Research; Ligands; Mediating; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Organ; Organoids; Pathway interactions; Physiological; Physiology; Play; Pre-Clinical Model; Probiotics; Production; Role; Ruminococcus; Serotonergic System; Serotonin; Signal Transduction; Testing; Therapeutic; Tissues; Tryptamines; Tryptophan; bacterial metabolism; base; commensal bacteria; gastrointestinal; gastrointestinal function; gut bacteria; gut microbes; gut microbiota; humanized mouse; in vivo; microbial; microbiota; novel; pathogenic bacteria; pre-clinical; receptor; self organization; self-renewal

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 preliminary studies have identified the gene tryptophan decarboxylase which converts dietary tryptophan to tryptamine in common human gut commensal bacteria like Ruminococcus gnavus and Clostridium sporogenes. Furthermore our preliminary data 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 receptor4 (5HT4R) antagonists and is absent in 5HT4R knock out mice. Interestingly genetically engineered bacteria with the gene tryptophan decarboxylase produce tryptamine in vivo in gnotobiotic mice and accelerate whole gut transit, when diet is supplemented with tryptophan. Our overall hypothesis is that dietary tryptophan driven production of bacterial tryptamine increases 5HT4R-mediated intestinal secretion modulating GI function in health and disease. In order to determine the mechanism of action of tryptamine we will first determine if the effect of exogenous tryptamine on intestinal secretion is dependent on 5HT4R and identify specific downstream pathways responsible for secretion. We will then investigate the effect of dietary tryptophan on bacteria produced tryptamine and 5HT4R mediated intestinal secretion and whole gut transit as well as its application in a preclinical model of constipation. The results from this study will potentially contribute to the development of novel engineered probiotics capable of producing a bioactive metabolite such as tryptamine to correct the altered physiology such as constipation in diseases like IBS.

抽象的 我们实验室研究的总体目标是 确定肠道菌群及其肠道的机制 产品改变胃肠道（GI）腔腔生理学和TO 发展基于微生物群的治疗性 纠正与肠易激综合症（IB）等疾病中生理改变的操作 肠道菌群的改变。我们的初步研究已经确定了色氨酸脱羧酶的基因 将饮食色氨酸转换为色氨酸，在普通的人类肠道共生细菌（如ruminococcus gnavus和梭状芽孢杆菌。此外，我们的初步数据表明，色胺增加了 电路电流（代表离子通量；替代分泌物）在体外遍布结肠上皮 室研究和这种作用可以被5-羟色胺受体4（5HT4R）拮抗剂抑制，并且不存在 5HT4R敲出老鼠。有趣的是，具有基因色氨酸脱羧酶的基因工程细菌 饮食补充时，在gnotobiotic小鼠中生产色素胺在gnotobirotic小鼠中并加速整个肠道过境 色氨酸。我们的总体假设是饮食色氨酸驱动的细菌色氨酸的产生增加 5HT4R介导的肠道分泌调节健康和疾病中的胃肠道功能。为了确定 色素作用机理我们将首先确定外源性色素对肠的影响是否是否 分泌取决于5HT4R，并确定负责分泌的特定下游途径。我们将 然后研究饮食色氨酸对细菌产生的色氨酸和5HT4R介导的影响 肠道分泌和整个肠道及其在便秘的临床前模型中的应用。这 这项研究的结果可能有助于发展能够的新型工程益生菌的发展 产生生物活性代谢物，例如色素，以纠正改变的生理学，例如便秘 像IBS这样的疾病。