Role of FODMAPs in the pathophysiology of diarrhea-predominant Irritable bowel syndrome

FODMAP 在腹泻型肠易激综合征病理生理学中的作用

• 批准号: 10670339
• 负责人: Prashant Singh
• 金额: $ 19.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670339
• 关键词: Affect; Cell Culture Techniques; Chronic Disease; Chronic diarrhea; Client satisfaction; Clinical; Clinical Research; Colon; Data; Diarrhea; Diet; Dietary Intervention; Digestive System Disorders; Disaccharides; Enterobacteriaceae; Epithelium; Family; Fructose; Functional disorder; Funding; Goals; Gram-Negative Bacteria; Growth; Health Care Costs; Human; In Vitro; International; Intervention; Irritable Bowel Syndrome; Knowledge; Lipopolysaccharides; Mediating; Mentors; Mentorship; Modeling; Molecular; Monosaccharides; Mucous Membrane; Mus; Myosin Light Chain Kinase; Oligonucleotides; Oligosaccharides; Outcome; PAR-2 Receptor; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Population; Precision Health; Precision therapeutics; Prevalence; Productivity; Regulation; Research; Research Personnel; Rodent; Rodent Model; Role; Severities; Signal Transduction; Source; Structure; Subgroup; Symptoms; TLR4 gene; Testing; Training; Translating; Tryptase; United States; United States National Institutes of Health; Work; antagonist; clinical translation; dysbiosis; fructooligosaccharide; human disease; improved; in vitro Model; in vivo; individualized medicine; ineffective therapies; mast cell; microbial; microbiome; microbiome alteration; microbiome analysis; novel strategies; polyol; precision medicine; recruit; responders and non-responders; skills; targeted treatment; translational approach; translational scientist

Abstract Diarrhea-predominant Irritable Bowel Syndrome (IBS-D) is the most common cause of chronic diarrhea in the United States. A diet high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) (HFM) induces symptoms in IBS-D patients and a diet low in FODMAPs (LFM) provides some symptomatic relief in ~50-60% of these patients. However, we do not understand how FODMAPs affect IBS-D symptoms. In this proposal, I plan to delineate the mechanisms of FODMAP-mediated IBS-D pathophysiology, which will help identify a subgroup of IBS-D patients with a distinct pathophysiologic pathway ultimately leading to targeted therapy with improved efficacy. My strong preliminary data suggest LFM reduces the fecal abundance of Akkermansiaceae and Enterobacteriaceae and LPS levels in IBS-D patients. Moreover, I found that LFM improves colonic barrier function and reduces mast cell activation in LFM-responsive IBS-D patients. Finally, my preliminary work from in vivo rodent models suggests that luminal LPS and mast cells play a critical role in the FODMAP-mediated colonic barrier loss. Based on these preliminary data, my overall hypothesis is that HFM increases fecal LPS levels by increasing the abundance of pathogenic gram-negative bacteria. This luminal LPS initiates colonic epithelial barrier loss and activates mast cells causing the release of tryptase which further potentiates colonic barrier loss. I will test these hypotheses in two specific aims: In specific aim 1, I will elucidate the contributions of FODMAPs in IBS-D pathophysiology by determining the effect of a strictly-controlled 4-week LFM on clinical features, relative and absolute abundance of fecal gram-negative bacteria (including those detailed above) and LPS, colonic barrier function, and mucosal mast cell activation in IBS-D patients and comparing the changes in these pathophysiologic parameters among LFM-responders and non-responders. In specific aim 2, I will define the mechanisms by which FODMAPs induce epithelial barrier loss and mast-cell activation in IBS-D. I will do so by applying IBS-D fecal supernatants (pre- and post-LFM) to human colonoids with/without TLR4 antagonists. In parallel, I will also apply fecal supernatants to mast cells from wild type and tlr4-/- mice to assess tryptase release. Finally, I will determine the contributions of PAR2 receptor and myosin light chain kinase signaling in tryptase-mediated barrier loss in human colonoid model. These aims will address current gaps in our understanding of IBS-D pathophysiology and provide mentored training in the assessment of in vivo and ex vivo epithelial barrier structure and function, microbiome analysis, and in vitro human colonoid model to study epithelial barrier regulation. My mentorship committee comprises of internationally renowned NIH-funded investigators with an exceptional track record of mentoring- Drs. Owyang (expert in IBS pathophysiology), Drs. Nusrat and Turner (experts in barrier function), and Dr. Schmidt (expert in microbiome). The mentored training will enable me to become an independent clinical-translational investigator defining IBS mechanisms and applying that knowledge in clinical studies to develop IBS precision therapies.

摘要 腹泻型肠易激综合征（IBS-D）是慢性腹泻的最常见原因， 美国的富含可发酵低聚糖、二糖、单糖和多元醇的饮食 （FODMAPs）（HFM）诱导IBS-D患者的症状，低FODMAPs（LFM）的饮食提供了一些 约50-60%的患者症状缓解。然而，我们不知道FODMAPs如何影响IBS-D 症状在这个提议中，我计划描述FODMP介导的IBS-D病理生理学机制， 这将有助于确定一个亚组的IBS-D患者与一个独特的病理生理途径，最终导致 以提高疗效的靶向治疗。我的初步数据显示LFM可以减少粪便 IBS-D患者中阿克曼氏菌科和肠杆菌科的丰度和LPS水平。此外，我发现 LFM改善了结肠屏障功能，减少了LFM应答性IBS-D患者中肥大细胞的活化。 最后，我在体内啮齿动物模型中的初步工作表明，管腔内脂多糖和肥大细胞在体内起着关键作用。 在FODMP介导的结肠屏障丧失中的作用。根据这些初步数据，我的总体假设是 HFM通过增加致病性革兰氏阴性菌的丰度来增加粪便LPS水平。这 管腔内LPS启动结肠上皮屏障丧失并激活肥大细胞，引起类胰蛋白酶的释放 这进一步增强了结肠屏障的丧失。我将在两个具体目标中检验这些假设： 1，我将阐明的贡献，FODMAPs在IBS-D病理生理学通过确定的影响， 严格控制的4周LFM对临床特征、粪便革兰氏阴性菌的相对和绝对丰度的影响 细菌（包括上面详述的那些）和LPS、结肠屏障功能和粘膜肥大细胞活化， IBS-D患者，并比较LFM应答者和 无应答者。在具体目标2中，我将定义FODMAPs诱导上皮屏障的机制， 在IBS-D中的损失和肥大细胞活化。我将通过将IBS-D粪便上清液（LFM前和LFM后） 具有/不具有TLR 4拮抗剂的人类结肠。与此同时，我还将粪便上清液应用于肥大细胞 以评估类胰蛋白酶释放。最后，我将确定PAR 2的贡献 受体和肌球蛋白轻链激酶信号在类胰蛋白酶介导的人类结肠模型屏障丧失中的作用。 这些目标将解决我们目前对IBS-D病理生理学理解的差距， 在体内和离体上皮屏障结构和功能评估，微生物组分析， 和体外人结肠模型来研究上皮屏障调节。我的导师委员会包括 国际知名的NIH资助的研究人员，具有出色的指导记录-Owyang博士 Nusrat和Turner博士（屏障功能专家）和施密特博士（屏障功能专家）。 微生物组）。指导培训将使我成为一个独立的临床翻译研究者 定义IBS机制，并将这些知识应用于临床研究，以开发IBS精确疗法。

项目成果

Prevalence and Associated Factors of Bloating: Results From the Rome Foundation Global Epidemiology Study.

腹胀的患病率和相关因素：罗马基金会全球流行病学研究的结果。

• DOI: 10.1053/j.gastro.2023.05.049
• 发表时间: 2023
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Ballou,Sarah;Singh,Prashant;Nee,Judy;Rangan,Vikram;Iturrino,Johanna;Geeganage,Grace;Löwe,Bernd;Bangdiwala,ShrikantI;Palsson,OlafurS;Sperber,AmiD;Lembo,Anthony;Lehmann,Marco
• 通讯作者: Lehmann,Marco

Effect of antibiotic pretreatment on bacterial engraftment after Fecal Microbiota Transplant (FMT) in IBS-D.

• DOI: 10.1080/19490976.2021.2020067
• 发表时间: 2022-01
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Singh P;Alm EJ;Kelley JM;Cheng V;Smith M;Kassam Z;Nee J;Iturrino J;Lembo A
• 通讯作者: Lembo A

Clinical Characteristics of Patients Presenting With Bloating as a Predominant Symptom.

以腹胀为主要症状的患者的临床特征。

• DOI: 10.1097/mcg.0000000000001767
• 发表时间: 2023
• 期刊: Journal of clinical gastroenterology
• 影响因子: 2.9
• 作者: Said,Hyder;Nee,Judy;Iturrino,Johanna;Rangan,Vikram;Singh,Prashant;Lembo,Anthony;Ballou,Sarah
• 通讯作者: Ballou,Sarah

Prevalence of Celiac Disease in Patients With Liver Diseases: A Systematic Review and Meta-Analyses.

肝病患者乳糜泻的患病率：系统评价和荟萃分析。

• DOI: 10.14309/ajg.0000000000002123
• 发表时间: 2023
• 期刊: The American journal of gastroenterology
• 作者: Yoosuf,Shakira;Singh,Prashant;Khaitan,Ashank;Strand,TorA;Ahuja,Vineet;Makharia,GovindK
• 通讯作者: Makharia,GovindK