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.

项目摘要/摘要 背景 - 微生物组主要通过合成或修改的代谢产生主机代谢 由肠道细菌。这些代谢产物的身份及其在宿主中的作用机理仍然很大程度上仍然很大 未知。总体代谢组学分析已瞥见一类微生物分子和 他们如何与疾病联系在一起。最近已经显示了两种类型的分子，胆汁酸和叶状 不同的年度调节细胞信号通路。但是，胆汁酸和 叶叶叶诱发肠道渗透性和炎症，代谢综合征的标志在很大程度上仍然存在。 研究 - 人类患者和炎症性疾病的啮齿动物模型的靶向代谢组分析将 与健康对照组相比，鉴定胆汁酸和叶酸代谢产物。初步数据表明 微生物未结合的胆汁酸会诱导肠道通透性，抑制其防止发育 非酒精性脂肪性肝炎（NASH）。胆汁酸被肠道细菌解偶。 K99阶段 提案将确定未结合的胆汁酸如何诱导肠道通透性的机制，以及慢性 抑制肠道细菌胆汁酸解偶会是挽救肠道渗透性和NASH的有效策略。 有足够的证据表明细菌产生的多谷氨酸（GLU）叶叶可以激活宿主 叶酸受体（FR）信号传导，进而诱导MAP激酶途径。 K99/R00过渡阶段 该提案将在激活FR的同类群中识别并量化单个叶酸分子。这 患病的样本包括啮齿动物和人类减肥手术，纳什和炎症性肠病（IBD） 肠内容物。将生成一个高通量筛选的叶酸复合库。炎症 叶酸产生细菌将被分离，以在菌株和肠道注射之间建立因果关系。 多个IBD患者回肠活检显示叶酸水解酶（FOLH1）基因的上调，唯一已知的 其目的是将二元二元叶状叶状变成单热形式。在R00阶段，叶酸的机理 IBD中FOLH1的介导的上调将研究。此外，多葡萄叶叶酸的作用将是 在肠道注射和代谢的背景下进行研究。线粒体动力学的改变，一 激活或抑制叶酸/fr/folh1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鉴定可以挽救肠道注射的分子。 对公共卫生的影响 - 肠道中的细菌遭遇胆汁和饮食营养，然后才能吸收 身体。从肠中吸收的胆汁酸和叶酸中约有50％是微生物衍生的。所以， 研究微生物组衍生的代谢产物及其活性不仅对肠道，而且对生物很重要 稳态。胆汁酸是肠道中最丰富的分子之一，以毫米浓度存在。 叶酸浓度，肠道也很高，基于不同 国家。因此，对疾病预后中这些代谢产物的研究将揭示改善策略。