Elucidating the role of the microbiome in inducing gut permeability and inflammation

阐明微生物组在诱导肠道通透性和炎症中的作用

• 批准号: 10370144
• 负责人: Snehal Nitin Chaudhari
• 金额: $ 9.15万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370144
• 关键词: Acute; Affect; Apoptosis; Attention; Automobile Driving; Bacteria; Bile Acids; Bile fluid; Binding Sites; Biochemical; Bioinformatics; Biological Assay; Biopsy; Carbon; Cells; Chronic; Cirrhosis; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Colon; Country; Coupled; Data; Development; Disease; Epithelial Cells; Fatty Liver; Feces; Folic Acid; General Hospitals; Genetic; Genetic Transcription; Germ-Free; Goals; Growth; Health; Homeostasis; Human; Hydrolase; In Vitro; Incubated; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Content; Intestinal permeability; Intestines; Libraries; Link; Liver; Liver Cirrhosis; Liver diseases; MAP Kinase Gene; Massachusetts; Measures; Mediating; Metabolic syndrome; Metabolism; Metagenomics; Mitochondria; Mitogen-Activated Protein Kinases; Morphology; Mus; Nutrient; Obesity; Pathogenesis; Pathway interactions; Patients; Phase; Phase Transition; Phenotype; Pilot Projects; Policies; Portal vein structure; Production; Prognosis; Proteins; Public Health; Rattus; Receptor Activation; Receptor Signaling; Research; Rodent; Rodent Model; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Targeted Research; Techniques; Testing; Therapeutic; Tight Junctions; Up-Regulation; Work; absorption; bariatric surgery; base; bile salts; choline deficient diet; cohort; comorbidity; dietary; disease prognosis; folate-binding protein; fortification; gastrointestinal epithelium; gut bacteria; gut inflammation; high throughput screening; ileum; in vivo evaluation; inhibitor; intestinal epithelium; intestinal homeostasis; macrophage; medical schools; metabolic engineering; metabolomics; microbial; microbiome; microbiome research; nonalcoholic steatohepatitis; novel; prevent; screening; small molecule; stool sample; therapeutic development; transcription factor

Project Summary/Abstract Background – The microbiome affects host metabolism predominantly via metabolites synthesized or modified by gut bacteria. The identity of these metabolites and their mechanisms of action in the host remain largely unknown. Overarching metabolomic analyses have offered a glimpse into classes of microbial molecules and how they associate with disease. Two such types of molecules, bile acids and folates have been shown in recent years to differentially modulate cell signaling pathways. However, the mechanisms of how distinct bile acids and folates induce gut permeability and inflammation, the hallmarks of metabolic syndrome remain largely evasive. Research – Targeted metabolomic analyses in human patient and rodent models of inflammatory diseases will identify bile acid and folate metabolites that differ compared to healthy controls. Preliminary data suggests that microbial unconjugated bile acids induce intestinal permeability, inhibition of which protects against development of Non-Alcoholic Steatohepatitis (NASH). Bile acids are deconjugated by gut bacteria. The K99 phase of the proposal will identify mechanisms of how unconjugated bile acids induce intestinal permeability, and if chronic inhibition of gut bacterial bile acid deconjugation is an effective strategy to rescue gut permeability and NASH. There is sufficient evidence to suggest that bacterially produced polyglutamylated (glu) folates can activate host folate receptor (FR) signaling, which in turn induces the MAP kinase pathway. The K99/R00 transition phase of the proposal will identify and quantify individual folate molecules in diseased cohorts that activate FR. The diseased samples include rodent and human bariatric surgery, NASH, and Inflammatory Bowel Disease (IBD) intestinal contents. A compound library of folates will be generated for high-throughput screening. Inflammatory folate producing bacteria will be isolated to establish causal relationships between strains and gut inflammation. Multiple IBD patient ileal biopsies show an upregulation of the folate hydrolase (FOLH1) gene, the only known purpose of which is to deconjugate poly-glu folates to mono-glu form. In the R00 phase, the mechanism of folate- mediated upregulation of FOLH1 in IBD will be studied. Further, the role of poly-glu folate deconjugation will be studied in the context of intestinal inflammation and metabolism. Alterations in mitochondrial dynamics, one- carbon metabolism, and energy status will be measured following activation or inhibition of the folate/FR/FOLH1 axis. This study will also utilize high-throughput screening to identify molecules that can rescue gut inflammation. Impact on Public Health – Bacteria in the gut encounter bile and dietary nutrients prior to their absorption in the body. Approximately 50% of bile acids and folates absorbed from the intestine is microbially derived. Therefore, studying microbiome-derived metabolites and their activity is important not only for intestinal, but organismal homeostasis. Bile acids are one of the most abundant molecules in the gut, present in millimolar concentrations. Folate concentrations, also high in the gut, vary widely based on folate fortification policies imposed by different countries. Therefore, the study of these metabolites in disease prognosis will reveal strategies for amelioration.

项目概要/摘要 背景——微生物群主要通过合成或修饰的代谢物影响宿主代谢 通过肠道细菌。这些代谢物的特性及其在宿主中的作用机制在很大程度上仍然存在 未知。总体代谢组学分析让我们得以了解微生物分子的类别和 他们如何与疾病联系起来。最近发现了两种这样的分子：胆汁酸和叶酸。 多年差异化调节细胞信号传导途径。然而，胆汁酸和胆汁酸的不同机制 叶酸会诱发肠道通透性和炎症，但代谢综合征的特征在很大程度上仍然被忽视。 研究——对人类患者和啮齿动物炎症性疾病模型进行有针对性的代谢组学分析 识别与健康对照不同的胆汁酸和叶酸代谢物。初步数据表明 微生物非结合胆汁酸诱导肠道通透性，抑制肠道通透性可防止发育 非酒精性脂肪性肝炎（NASH）。胆汁酸被肠道细菌分解。 K99阶段 该提案将确定非结合胆汁酸如何诱导肠道通透性的机制，以及如果慢性 抑制肠道细菌胆汁酸解结合是挽救肠道通透性和 NASH 的有效策略。 有足够的证据表明细菌产生的聚谷氨酰化 (glu) 叶酸可以激活宿主 叶酸受体 (FR) 信号传导，进而诱导 MAP 激酶途径。 K99/R00过渡阶段 该提案将识别并量化患病人群中激活 FR 的单个叶酸分子。这 患病样本包括啮齿动物和人类减肥手术、NASH 和炎症性肠病 (IBD) 肠内容物。将生成叶酸化合物库用于高通量筛选。炎症 将分离产生叶酸的细菌，以建立菌株与肠道炎症之间的因果关系。 多个 IBD 患者回肠活检显示叶酸水解酶 (FOLH1) 基因上调，这是唯一已知的基因 其目的是将聚谷氨酸叶酸分解为单谷氨酸形式。在 R00 阶段，叶酸的作用机制是 将研究 IBD 中 FOLH1 介导的上调。此外，聚谷氨酸叶酸解结合的作用将是 在肠道炎症和代谢的背景下进行研究。线粒体动力学的改变，一 叶酸/FR/FOLH1激活或抑制后将测量碳代谢和能量状态 轴。这项研究还将利用高通量筛选来识别可以挽救肠道炎症的分子。 对公共健康的影响——肠道中的细菌在被肠道吸收之前会遇到胆汁和膳食营养素。 身体。从肠道吸收的胆汁酸和叶酸大约 50% 来自微生物。所以， 研究微生物组衍生的代谢物及其活性不仅对肠道很重要，而且对生物体也很重要 体内平衡。胆汁酸是肠道中最丰富的分子之一，以毫摩尔浓度存在。 肠道中的叶酸浓度也很高，根据不同国家实施的叶酸强化政策，叶酸浓度差异很大。 国家。因此，对这些代谢物在疾病预后中的研究将揭示改善策略。