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.

项目总结/文摘

项目成果

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.

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

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.

益生菌降低了早产，低出生体重婴儿的死亡率和发病率：对随机试验的系统评价和网络荟萃分析。

• 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

Role of gut microbiota in regulating gastrointestinal dysfunction and motor symptoms in a mouse model of Parkinson's disease.

• DOI: 10.1080/19490976.2020.1866974
• 发表时间: 2021-01-01
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Bhattarai Y;Si J;Pu M;Ross OA;McLean PJ;Till L;Moor W;Grover M;Kandimalla KK;Margolis KG;Farrugia G;Kashyap PC
• 通讯作者: Kashyap PC