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: 10675092
• 负责人: Purna C Kashyap
• 金额: $ 59.12万
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675092
• 关键词: Abdomen; Acceleration; Address; Adrenergic Receptor; Affect; Bacteria; Biological; Butyrates; Categories; Cations; Cell Culture Techniques; Cell Line; Cell physiology; Colon; Complex; Constipation; Consumption; Data; Development; Diarrhea; Disease; Dopamine; Economic Burden; Encapsulated; Enterochromaffin Cells; Epigenetic Process; Feces; Frequencies; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gastrointestinal Motility; Gastrointestinal Physiology; Gastrointestinal Transit; Gene Expression; Germ-Free; Gnotobiotic; Go Alpha Subunit; Grant; Health Care Costs; Histone Acetylation; Hypoxanthines; Image; In Vitro; Individual; Inflammation; Irritable Bowel Syndrome; Knowledge; Ligands; Link; Methods; Molecular; Mucous body substance; Mus; Neurons; Norepinephrine; Opitz trigonocephaly syndrome; Organoids; Outcome; Pain; Pathway interactions; Patients; Physiological; Play; Population; Preparation; Probiotics; Purinergic P1 Receptors; Quality of life; Research; Rodent Model; Role; Serotonin; Signal Transduction; Site-Directed Mutagenesis; Testing; Therapeutic; Transgenic Mice; Tryptamines; adenosine receptor activation; design; epigenomics; gastrointestinal function; gut bacteria; gut microbes; human study; in vivo; member; microbial; microbial based therapy; microbial products; mouse model; multiple omics; mutant; novel; probiotic therapy; productivity loss; receptor; receptor expression; response; targeted treatment; transcriptomics

PROJECT SUMMARY/ABSTRACT Irritable bowel syndrome (IBS) is a globally prevalent disorder (~11%) characterized by an alteration in stool form/frequency in association with abdominal discomfort or pain. IBS is categorized into constipation, diarrhea or mixed (IBS-C, IBD-D, IBS-M) based on the predominant stool form/frequency. The pathophysiology of IBS is complex and therapeutic options targeting the underlying pathophysiology in IBS are limited. Recent studies support a role for gut microbial metabolites in maintaining normal gastrointestinal (GI) function, but how changes in different microbial metabolites and interactions among these metabolites affect molecular pathways involved in IBS pathophysiology remains a critical knowledge gap. Hence, it is not surprising that the current empirically designed microbial therapies (probiotics) have largely proven ineffective in IBS. To address this gap, in the previous grant cycle we focused on the bacterial metabolite tryptamine and found tryptamine increases secretion and mucus release in a 5- HT4R dependent manner, accelerates transit, and protects against inflammation in rodent models. The observations were supported by our finding of elevated levels of tryptamine in IBS-D in our human study. In the same longitudinal multi-omics human study, the most consistent finding in IBS-C across multiple -omics platforms were significant decreases in stool hypoxanthine and butyrate. The overall objective of this proposal is to determine the physiologic relevance of these metabolites by identifying the molecular pathways affected by each of these metabolites that are relevant to IBS-C. Our central hypothesis based on prior research and our preliminary data is that hypoxanthine is an effector metabolite that accelerates GI transit by increasing enterochromaffin (EC) cell serotonin release while butyrate is a regulatory metabolite that augments the biologic activity of effector metabolites. This will be tested in two Aims: In Aim 1, we will determine the mechanism by which hypoxanthine increases EC cell serotonin release and accelerates GI transit and in Aim 2, we will determine the mechanism by which butyrate regulates EC cell responses to effector metabolites and the resultant effects on GI function. We will use Ca2+ imaging in organoids/primary EC cell culture from novel transgenic mice, heterologous receptor expression with site- directed mutagenesis, and epigenomic and transcriptomics data, combined with ex vivo colon preparations, gnotobiotic- and EC cell-depleted mouse models, isogenic bacterial mutants, and novel encapsulation methods to address the above aims. Our findings will uncover specific pathways by which these microbial metabolites affect GI transit and allow development of novel mechanism-based microbial therapies for IBS-C.

项目概要/摘要 肠易激综合征 (IBS) 是一种全球流行的疾病 (~11%)，其特征是肠易激综合征 (IBS) 发生改变 与腹部不适或疼痛相关的大便形式/频率。 IBS 分为 根据主要粪便形式/频率，便秘、腹泻或混合型（IBS-C、IBD-D、IBS-M）。这 IBS 的病理生理学很复杂，针对 IBS 潜在病理生理学的治疗选择 是有限的。最近的研究支持肠道微生物代谢物在维持正常肠道菌群中的作用 胃肠道（GI）功能，但不同微生物代谢物的变化及其相互作用 这些代谢物影响 IBS 病理生理学相关的分子途径仍然是一个关键知识 差距。因此，当前根据经验设计的微生物疗法（益生菌）具有效果也就不足为奇了。 大部分被证明对 IBS 无效。为了解决这一差距，在上一个资助周期中，我们重点关注 细菌代谢物色胺，发现色胺增加 5- 的分泌和粘液释放 在啮齿动物模型中，HT4R 依赖性方式可加速转运并防止炎症。这 我们在人体研究中发现 IBS-D 中色胺水平升高，这支持了我们的观察。在 相同的纵向多组学人类研究，跨多个组学的 IBS-C 最一致的发现 平台上粪便次黄嘌呤和丁酸盐显着减少。本次活动的总体目标 建议通过鉴定分子来确定这些代谢物的生理相关性 受与 IBS-C 相关的每种代谢物影响的途径。我们的中心假设基于 根据先前的研究和我们的初步数据，次黄嘌呤是一种效应代谢物， 通过增加肠嗜铬 (EC) 细胞血清素的释放来加速胃肠道转运，而丁酸盐是一种调节剂 增强效应代谢物生物活性的代谢物。这将在两个目标中进行测试： 目标 1，我们将确定次黄嘌呤增加 EC 细胞血清素释放的机制 加速胃肠道转运，在目标 2 中，我们将确定丁酸盐调节 EC 细胞的机制 对效应代谢物的反应及其对胃肠道功能的影响。我们将使用 Ca2+ 成像 来自新型转基因小鼠的类器官/原代 EC 细胞培养物，异源受体表达位点- 定向诱变、表观基因组和转录组学数据，结合离体结肠 制剂、无菌和 EC 细胞耗尽的小鼠模型、同基因细菌突变体和新型 封装方法可以实现上述目标。我们的研究结果将揭示具体的途径 这些微生物代谢物影响胃肠道运输并允许开发基于新机制的微生物 IBS-C 的治疗。

项目成果

Model of personalized postprandial glycemic response to food developed for an Israeli cohort predicts responses in Midwestern American individuals.

为以色列队列开发的个性化餐后血糖反应模型可以预测美国中西部个体的反应。

• 发表时间: 2019-07-01
• 作者: Mendes;Raveh;Azulay, Shahar;Ben;Cohen, Yossi;Ofek, Tal;Stevens, Josh;Bachrach, Davidi;Kashyap, Purna;Segal, Lihi;Nelson, Heidi
• 通讯作者: Nelson, Heidi

Functional Gastrointestinal Disorders and the Microbiome-What Is the Best Strategy for Moving Microbiome-based Therapies for Functional Gastrointestinal Disorders into the Clinic?

功能性胃肠道疾病和微生物组——将基于微生物组的功能性胃肠道疾病疗法引入临床的最佳策略是什么？

• 发表时间: 2021
• 影响因子: 29.4
• 作者: Mars, Ruben A T;Frith, Mary;Kashyap, Purna C
• 通讯作者: Kashyap, Purna C

Adjustable Intragastric Balloon Leads to Significant Improvement in Obesity-Related Lipidome and Fecal Microbiome Profiles: A Proof-of-Concept Study.

可调节胃内气球可显着改善与肥胖相关的脂质组和粪便微生物组特征：概念验证研究。

• 发表时间: 2022-07-01
• 作者: Hussan, Hisham;Abu Dayyeh, Barham K;Chen, Jun;Johnson, Stephen;Riedl, Ken M;Grainger, Elizabeth M;Brooks, Jeffrey;Hinton, Alice;Simpson, Christina;Kashyap, Purna C
• 通讯作者: Kashyap, Purna C

Role of Diet-Microbiome Interaction in Gastrointestinal Disorders and Strategies to Modulate Them with Microbiome-Targeted Therapies.

饮食-微生物组相互作用在胃肠道疾病中的作用以及通过微生物组靶向治疗调节它们的策略。

• 发表时间: 2023-08-21
• 作者: Jadhav, Ajita;Bajaj, Aditya;Xiao, Yang;Markandey, Manasvini;Ahuja, Vineet;Kashyap, Purna C
• 通讯作者: Kashyap, Purna C

Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials.

益生菌降低早产、低出生体重婴儿的死亡率和发病率：随机试验的系统回顾和网络荟萃分析。

• 发表时间: 2020
• 影响因子: 29.4
• 作者: Morgan, Rebecca L;Preidis, Geoffrey A;Kashyap, Purna C;Weizman, Adam V;Sadeghirad, Behnam;McMaster Probiotic, Prebiotic, and Synbiotic Work Group
• 通讯作者: McMaster Probiotic, Prebiotic, and Synbiotic Work Group