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: 10542391
• 负责人: Snehal Nitin Chaudhari
• 金额: $ 9万
• 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 2023-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542391
• 关键词: Acute; Affect; 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; Induction of Apoptosis; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Absorption; Intestinal Content; Intestinal permeability; Intestines; Libraries; Link; Liver; Liver Cirrhosis; Liver diseases; MAP Kinase Gene; Macrophage; 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; 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; inflammatory modulation; inhibitor; intestinal epithelium; intestinal homeostasis; 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.

项目总结/摘要 背景-微生物组主要通过合成或修饰的代谢物影响宿主代谢 被肠道细菌感染这些代谢物的身份及其在宿主中的作用机制在很大程度上仍然是未知的。 未知全面的代谢组学分析提供了对微生物分子类别的一瞥， 它们与疾病的关系最近已经发现了两种这样的分子，胆汁酸和叶酸。 多年来差异调节细胞信号通路。然而，不同的胆汁酸和 叶酸诱导肠道渗透性和炎症，代谢综合征的标志仍然很大程度上是模糊的。 研究-在人类患者和啮齿动物炎症性疾病模型中进行靶向代谢组学分析将 鉴定与健康对照相比不同的胆汁酸和叶酸代谢物。初步数据提示 微生物非结合胆汁酸诱导肠通透性，抑制其可防止发育 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， 抑制肠道细菌胆汁酸去缀合是拯救肠道通透性和NASH的有效策略。 有足够的证据表明，细菌产生的多聚谷氨酰化（Glu）叶酸可以激活宿主 叶酸受体（FR）信号传导，其又诱导MAP激酶途径。K99/R 00过渡阶段 该提案将确定和量化激活FR的患病队列中的单个叶酸分子。 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文库用于高通量筛选。炎性 将分离产生叶酸的细菌以建立菌株和肠道炎症之间的因果关系。 多名IBD患者的回肠活检显示唯一已知的叶酸水解酶（FOLH 1）基因上调 其目的是将聚葡萄糖叶酸解偶联为单葡萄糖形式。在R 00阶段，叶酸- 将研究IBD中FOLH 1介导的上调。此外，聚谷氨酸叶酸解缀合的作用将是 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，一是- 将在叶酸/FR/FOLH 1激活或抑制后测量碳代谢和能量状态 轴线这项研究还将利用高通量筛选来鉴定可以拯救肠道炎症的分子。 对公共卫生的影响-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%是微生物来源的。因此，我们认为， 研究微生物组衍生的代谢物及其活性不仅对肠道， 体内平衡胆汁酸是肠道中含量最丰富的分子之一，以毫摩尔浓度存在。 叶酸浓度在肠道中也很高，根据不同国家的叶酸强化政策而变化很大。 国家因此，研究这些代谢物在疾病预后中的作用将揭示改善的策略。