Novel synthetic analogue of microbial metabolite, Urolithin A, mitigates inflammatory bowel diseases

微生物代谢物尿石素 A 的新型合成类似物可减轻炎症性肠病

• 批准号: 9415573
• 负责人: Venkatakrishna Rao Jala
• 金额: $ 21.56万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9415573
• 关键词: Acids; Acute; Affect; Anti-inflammatory; Bacteria; Benzopyrans; Berry; Biological; Biological Availability; Cells; Chemopreventive Agent; Chronic; Clinical; Colitis; Crohn' s disease; Data; Development; Diet; Dietary Intervention; Dietary Practices; Disease; Disease model; Dose; Down-Regulation; Ellagi-Tannins; Ellagic Acid; Epithelial; Epithelial Cells; Erythroid; Event; Exhibits; Functional disorder; Glycols; Goals; Heme; Homeostasis; Human; Ileitis; Immune; In Vitro; Indigenous; Individual; Individual Differences; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1; Interleukin-6; Intestinal permeability; Lipopolysaccharides; Measures; Mediating; Modeling; Molecular; Mus; Nuclear; Oral Administration; Oxygenases; Parents; Pathogenicity; Pathway interactions; Phenotype; Phytochemical; Pilot Projects; Pomegranate; Pre-Clinical Model; Probiotics; Production; Proteins; Risk; Role; Sampling; Sodium Dextran Sulfate; Structure; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Uses; Tight Junctions; Time; Treatment Efficacy; Trinitrobenzenesulfonic Acid; Ulcerative Colitis; Variant; analog; bacterial metabolism; base; chemokine; comparative efficacy; dysbiosis; gut bacteria; gut microbiota; in vivo; in vivo Model; inter-individual variation; microbial; microbiome research; microbiota metabolites; molecular targeted therapies; novel; protective effect

Project Summary/Abstract Inflammatory Bowel Diseases (IBDs), which include f ulcerative colitis and Crohn’s disease, affect as many as 1.4 million people in the USA. Chronic inflammation and microbial dysbiosis are major features of IBDs. Beneficial effects rendered by healthy dietary practices are not uniform among individuals and are attributed to variations in gut microbiota and their active metabolites. To overcome the challenge of inter-individual differences in gut microbiota, their metabolites and poor bioavailability, here we propose direct usage of microbial metabolites to maintain gut immune homeostasis to mitigate IBDs. Urolithin A (UroA) is one of such beneficial microbial metabolite derived from ellagic acid and ellagitannins, major polyphenolic components of berries and pomegranate. Based on UroA structure, we developed novel potent structural analogue, UAS03, which exhibited increased anti-inflammatory and gut barrier functional activities compared to parent UroA compound. The current proposal investigates the molecular and cellular mechanisms of UAS03 and its therapeutic efficacies in IBD pre-clinical models. Our preliminary results showed that the oral administration of UAS03 mitigated colitis in dextran sodium sulphate (DSS)- or 2,4,6-Trinitrobenzenesulfonic acid (TNBS) induced murine colitis even at 10 fold lower dose compared to UroA. UAS03 significantly inhibited lipopolysaccharide (LPS)-induced increase in inflammatory mediators in immune cells and epithelial cells with 10 fold higher efficacy than UroA. Further, treatment with UAS03 reduced intestinal permeability by up-regulating junctional proteins through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-hemoxygenase (HO1) pathways in epithelial cells. Based on these results, we propose two-pronged beneficial activities of UAS03 and UroA, where these compounds protect the host from external challenges by protecting gut barrier function and dampening inflammatory activities. In this proposal we will test the hypothesis that ‘treatment with UAS03, an effective analogue of a microbial metabolite, protects from IBD development by reducing barrier dysfunction and inflammation. In Aim 1, we will investigate how USA03/UroA increase gut barrier function in a Nrf2-dependent manner by upregulating junctional proteins as well as molecular events involved anti-inflammatory activities of UAS03. In Aim 2, therapeutic efficacies of UAS03 and UroA will be examined in acute, chronic and spontaneous IBD pre-clinical models. In Aim 3, we propose to identify the bacteria responsible for UroA production and test their pro-biotic activities in colitis models. The successful completion of proposed studies will allow understanding of UAS03 and UroA mechanisms of actions, and establishes the basis for therapeutic usage in IBDs.

项目概要/摘要 炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，影响 在美国，有多达 140 万人患有 IBD，其中慢性炎症和微生物失调是其主要特征。 健康饮食习惯所带来的有益效果在个体之间并不一致，这归因于 肠道微生物群及其活性代谢物的变化克服个体间差异的挑战。 在肠道微生物群中，它们的代谢物和生物利用度差，在这里我们建议直接使用微生物 维持肠道免疫稳态以减轻 IBD 的代谢物就是其中之一。 源自鞣花酸和鞣花单宁的微生物代谢物，鞣花酸和鞣花单宁是浆果和浆果的主要多酚成分 基于石榴的 UroA 结构，我们开发了新型有效的结构类似物 UAS03，其表现出 与母体 UroA 化合物相比，抗炎和肠道屏障功能活性增强。 目前的提案研究了 UAS03 的分子和细胞机制及其治疗功效 IBD 临床前模型。 我们的初步结果表明，口服UAS03可减轻右旋糖酐钠中的结肠炎 即使剂量低 10 倍，硫酸盐 (DSS) 或 2,4,6-三硝基苯磺酸 (TNBS) 也会诱发小鼠结肠炎 与 UroA 相比，UAS03 显着抑制脂多糖 (LPS) 诱导的炎症增加。 免疫细胞和上皮细胞中的介质，其疗效比 UroA 高 10 倍。 UAS03 通过激活核因子上调连接蛋白来降低肠道通透性 基于这些结果，我们研究了上皮细胞中的（红细胞源性 2）样 2 (Nrf2)-血氧合酶 (HO1) 通路。 提出 UAS03 和 UroA 的双管齐下的有益活性，其中这些化合物可以保护宿主免受 在本提案中，我们通过保护肠道屏障功能和抑制炎症活动来应对外部挑战。 将检验以下假设：“用 UAS03（一种微生物代谢物的有效类似物）治疗可保护 在目标 1 中，我们将研究如何通过减少屏障功能障碍和炎症来预防 IBD 的发展。 USA03/UroA 通过上调连接蛋白以 Nrf2 依赖性方式增加肠道屏障功能 以及涉及 UAS03 抗炎活性的分子事件。在目标 2 中，UAS03 的治疗效果。 在目标 3 中，我们将在急性、慢性和自发性 IBD 临床前模型中检查 UAS03 和 UroA。 建议鉴定负责产生 UroA 的细菌，并在结肠炎模型中测试其益生菌活性。 拟议研究的成功完成将有助于了解 UAS03 和 UroA 机制 行动，并为 IBD 的治疗应用奠定基础。