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.

项目摘要/摘要 肠易激综合征（IBS）是一种全球流行障碍（〜11％），其特征是改变 粪便形式/频率与腹部不适或疼痛有关。 IBS分类为 便秘，腹泻或混合（IBS-C，IBD-D，IBS-M）基于主要的粪便形式/频率。这 IBS的病理生理是针对IBS基础病理生理的复杂和治疗选择 有限。最近的研究支持肠道微生物代谢物在维持正常状态中的作用 胃肠道（GI）功能，但如何变化不同的微生物代谢产物和相互作用 这些代谢产物影响IBS病理生理学中涉及的分子途径仍然是关键知识 差距。因此，毫不奇怪，当前经验设计的微生物疗法（益生菌）具有 在IBS中，在很大程度上被证明无效。为了解决这一差距，在上一个赠款周期中，我们关注 细菌代谢产物色氨酸并发现色氨酸在5--中增加了分泌和粘液释放 HT4R依赖性方式，加速运输并预防啮齿动物模型中的炎症。这 在人类研究中，我们在IBS-D中发现色素水平升高的发现得到了观察。在 相同的纵向多摩斯人类研究，这是IBS-C中最一致的发现 粪便低黄嘌呤和丁酸酯的平台显着下降。总体目标 建议是通过鉴定分子来确定这些代谢产物的生理相关性 受IBS-C相关的每种代谢产物影响的途径。我们的中心假设 关于先前的研究和我们的初步数据，是黄黄嘌呤是一种效应代谢物，它是 通过增加肠胆素蛋白（EC）细胞5-羟色胺释放来加速胃肠道传输，而丁酸是一种调节性的 代谢物增强了效应代谢产物的生物学活性。这将以两个目的进行测试：目的 1，我们将确定低黄嘌呤增加EC细胞5-羟色胺释放和 加速GI运输，在AIM 2中，我们将确定丁酸酯调节EC细胞的机制 对效应子代谢产物的反应以及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，异源受体表达的器官/原发性EC细胞培养 定向诱变，表观基因组学和转录组学数据与离体结肠结合 制剂，gnotobiotic和EC细胞的小鼠模型，等生细菌突变体以及新型 解决上述目的的封装方法。我们的发现将发现特定的途径 这些微生物代谢产物影响胃肠道运输并允许开发基于机制的微生物 IBS-C的疗法。

项目成果

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

• DOI: 10.1146/annurev-nutr-061121-094908
• 发表时间: 2023-08-21
• 期刊: Annual review of nutrition
• 影响因子: 8.9

Small Intestinal Bacterial Overgrowth Complicating Gastrointestinal Manifestations of Systemic Sclerosis: A Systematic Review and Meta-analysis.

• DOI: 10.5056/jnm22168
• 发表时间: 2023-04-30
• 期刊: Journal of neurogastroenterology and motility
• 影响因子: 3.4
• 作者: Shah A;Pakeerathan V;Jones MP;Kashyap PC;Virgo K;Fairlie T;Morrison M;Ghoshal UC;Holtmann GJ
• 通讯作者: Holtmann GJ

Parkinson's disease: Are gut microbes involved?

• DOI: 10.1152/ajpgi.00058.2020
• 发表时间: 2020-11-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
• 影响因子: 4.5
• 作者: Bhattarai, Yogesh;Kashyap, Punta C.
• 通讯作者: Kashyap, Punta C.

Wild primate microbiomes prevent weight gain in germ-free mice.

• DOI: 10.1186/s42523-020-00033-9
• 发表时间: 2020-05-07
• 期刊: Animal microbiome
• 影响因子: 4.7
• 作者: Sidiropoulos DN;Al-Ghalith GA;Shields-Cutler RR;Ward TL;Johnson AJ;Vangay P;Knights D;Kashyap PC;Xian Y;Ramer-Tait AE;Clayton JB
• 通讯作者: Clayton JB

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

• DOI: 10.1053/j.gastro.2020.05.096
• 发表时间: 2020-08
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Morgan RL;Preidis GA;Kashyap PC;Weizman AV;Sadeghirad B;McMaster Probiotic, Prebiotic, and Synbiotic Work Group
• 通讯作者: McMaster Probiotic, Prebiotic, and Synbiotic Work Group