Use of tryptophan-synthesizing bacteria to enhance intestinal motility

利用色氨酸合成菌增强肠道蠕动

• 批准号: 10453687
• 负责人: Brigitte Lavoie
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453687
• 关键词: Agonist; Applications Grants; Aromatic-L-Amino-Acid Decarboxylases; Bacillus subtilis; Bacteria; Behavior; Biochemical; Blood specimen; Brain; Cell Degranulation; Cells; Chemicals; Clostridium difficile; Constipation; Diarrhea; Diet; Digestion; Digestive System Disorders; Disease; Drug Targeting; Elements; Endocrine Glands; Enteral; Enterobacteriaceae; Enterochromaffin Cells; Epithelial; Epithelial Cells; Essential Amino Acids; Formulation; Future; Gastric Emptying; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal tract structure; Genes; Goals; Goblet Cells; Health; Human; Hydroxyindoleacetic Acid; Indoles; Infection; Inflammatory; Inflammatory Bowel Diseases; Intestinal Motility; Intestinal Secretions; Intestines; Investigation; Knowledge; Kynurenine; Large Intestine; Link; Location; Measures; Mediating; Motor; Mucous Membrane; Mus; Nausea and Vomiting; Neurons; Outcome Measure; Patients; Pattern; Pharmacology; Physiological Processes; Population; Probiotics; Production; Property; Proteins; Recurrence; Reflex action; Reporter; Research Design; Role; Serotonin; Serotonin Receptors 5-HT4; Signal Transduction; Signaling Molecule; Small Intestines; Societies; Source; Symptoms; Testing; Tissues; Transgenic Organisms; Tryptamines; Tryptophan; Tryptophan 5-monooxygenase; Tryptophan Synthase; Waste Products; Water; base; cell motility; design; dietary; effective therapy; fecal transplantation; gut bacteria; gut microbiome; gut microbiota; improved; innovation; intestinal epithelium; microbiome; microbiota; microorganism; neurochemistry; novel; novel strategies; optogenetics; probiotic therapy; receptor; response; serotonin receptor; spatiotemporal; success; symptom treatment; targeted treatment; translational approach; treatment strategy; virtual

Project Summary/Abstract Functional and inflammatory disorders of the gastrointestinal tract represent a significant burden to patients and to society. These disorders are difficult to treat, and recurrence of symptoms is common. As a result, there are ongoing efforts to develop more effective treatment options. The gut microbiome is now recognized as a dynamic entity that can influence a wide variety of physiological processes, ranging from the integrity of the intestinal epithelial barrier to brain neurochemistry and behavior. The clear success of fecal microbiome transplants in the treatment of C. difficile infections has highlighted the potential of utilizing the microbiome as a means of improving health. The studies that are included in this grant application are designed to exploit specific biochemical properties of certain bacterial strains to test novel treatment strategies for functional bowel disorders. We will test the hypothesis that tryptophan-synthesizing bacteria increase active tryptophan metabolites that enhance colonic motility through the activation of 5-HT4 receptors. Tryptophan is an essential amino acid that is typically acquired from the diet, but can also be produced by enteric bacteria. In addition to being incorporated into proteins, it serves as a precursor molecule for serotonin (5-HT), or it can be enzymatically converted to form kynurenine and its derivatives. In the epithelium of the intestine, enterochromaffin cells convert tryptophan to 5-HT. When 5-HT is released from these cells it triggers enteric reflexes that increase propulsive motility and epithelial secretion. Changes in 5-HT signaling have been identified in functional and inflammatory conditions of the gut, and drugs targeting 5-HT receptors have been developed for the treatment of constipation and diarrhea. In Specific Aim 1 of this proposal, we will test the hypothesis that treatment of mice with a bacterial strain that is known to produce tryptophan, and which has been used safely in probiotic formulations, results in increased mucosal 5- HT levels and enhanced intestinal motility. Specific Aim 2 of this proposal is aimed at determining the mechanisms by which tryptophan producing bacteria promote motility. The 5-HT receptor that is most directly linked to propulsive motility is the 5-HT4 receptor. We will test whether this receptor is involved and determine what tissues express the receptor that mediate this effect. We will also examine what changes in motility patterns and neuronal activity are associated with enhanced propulsive motility, and we will test whether increasing the tryptophan metabolite, tryptamine, can enhance the motility augmenting effect of tryptophan-producing bacteria. The results of these studies could provide a predictive translational strategy for the use of probiotic bacteria, with known biochemical features, for the treatment of constipation.

项目概要/摘要 胃肠道的功能性和炎症性疾病给患者带来了巨大的负担 和社会。这些疾病很难治疗，并且症状复发很常见。因此， 目前正在努力开发更有效的治疗方案。肠道微生物群现已被认识 作为一个动态实体，可以影响多种生理过程，从完整性到 肠上皮屏障对大脑神经化学和行为的影响。粪便微生物组的明显成功 移植治疗艰难梭菌感染凸显了利用微生物组作为治疗手段的潜力 改善健康的手段。本拨款申请中包含的研究旨在利用 某些细菌菌株的特定生化特性，以测试功能性肠道的新治疗策略 失调。我们将检验色氨酸合成细菌增加活性色氨酸的假设 通过激活 5-HT4 受体增强结肠蠕动的代谢物。 色氨酸是一种必需氨基酸，通常从饮食中获取，但也可以通过以下方式产生 肠道细菌。除了掺入蛋白质外，它还充当血清素的前体分子 (5-HT)，或者可以通过酶促转化形成犬尿氨酸及其衍生物。 在肠上皮中，肠嗜铬细胞将色氨酸转化为 5-HT。当 5-HT 为 从这些细胞中释放出来，它会触发肠反射，从而增加推进动力和上皮分泌。 5-HT 信号传导的变化已在肠道功能和炎症状况以及药物中被发现 靶向 5-HT 受体的药物已被开发用于治疗便秘和腹泻。特定目标 在该提案的第 1 部分中，我们将测试以下假设：用已知的细菌菌株治疗小鼠 产生色氨酸，并已安全地用于益生菌制剂中，导致粘膜 5- HT 水平和增强的肠道蠕动。 该提案的具体目标 2 旨在确定色氨酸产生的机制 细菌促进运动。与推进动力最直接相关的 5-HT 受体是 5-HT4 受体。我们将测试该受体是否参与其中，并确定哪些组织表达该受体 介导这种效应。我们还将检查运动模式和神经元活动的变化 与增强的推进动力相关，我们将测试是否增加色氨酸代谢物， 色胺，可增强产色氨酸细菌的运动增强作用。 这些研究的结果可以为益生菌的使用提供预测性转化策略 具有已知生化特征的细菌，用于治疗便秘。

项目成果

Interplay of Broccoli/Broccoli Sprout Bioactives with Gut Microbiota in Reducing Inflammation in Inflammatory Bowel Diseases.

• DOI: 10.1016/j.jnutbio.2022.109238
• 发表时间: 2022-11
• 期刊: The Journal of nutritional biochemistry
• 作者: Johanna M. Holman;Molly Hurd;P. Moses;G. Mawe;Zhang Tao;S. Ishaq;Yanyan Li

Monitoring Gut Epithelium Serotonin and Melatonin Overflow Provides Spatial Mapping of Inflammation.

• DOI: 10.1002/cbic.202200334
• 发表时间: 2023-01-17
• 期刊: Chembiochem : a European journal of chemical biology

Direct and indirect mechanisms by which the gut microbiota influence host serotonin systems.

• DOI: 10.1111/nmo.14346
• 发表时间: 2022-10
• 期刊: NEUROGASTROENTEROLOGY AND MOTILITY
• 影响因子: 3.5
• 作者: Legan, Theresa B.;Lavoie, Brigitte;Mawe, Gary M.
• 通讯作者: Mawe, Gary M.

Tryptophan-synthesizing bacteria enhance colonic motility.

色氨酸合成细菌增强结肠蠕动。

• DOI: 10.1111/nmo.14629
• 发表时间: 2023
• 期刊: Neurogastroenterology and motility
• 影响因子: 3.5
• 作者: Legan,TheresaB;Lavoie,Brigitte;Norberg,Emilia;Ley,IsabellaC;Tack,Stephanie;Tompkins,ThomasA;Wargo,MatthewJ;Mawe,GaryM
• 通讯作者: Mawe,GaryM