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: 10349569
• 负责人: Venkatakrishna Rao Jala
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349569
• 关键词: Acids; Acute; Affect; Anti-Inflammatory Agents; 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 Attachment; 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; Persons; 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; Wild Type Mouse; analog; bacterial metabolism; base; chemokine; comparative efficacy; dysbiosis; efficacy evaluation; gastrointestinal epithelium; gut bacteria; gut microbiota; in vivo; in vivo Model; inter-individual variation; macrophage; microbial; microbiome research; microbiota metabolites; molecular targeted therapies; murine colitis; novel; preservation; protective effect; translational potential

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.

项目摘要/摘要 炎症性肠道疾病（IBD），包括溃疡性结肠炎和克罗恩病，影响为 美国有140万人。慢性感染和微生物营养不良是IBD的主要特征。 健康饮食习俗产生的有益影响在个人中并不统一，归因于 肠道菌群及其活性代谢产物的变化。克服个人间差异的挑战 在肠道微生物群中，它们的代谢产物和差的生物利用度，在这里我们提出直接使用微生物 保持肠道免疫稳态以减轻IBD的代谢产物。 urolithin a（uroa）是这样有益的之一 微生物代谢物衍生自椭圆酸和椭圆丁素，浆果的主要多酚成分和 石榴。基于UROA结构，我们开发了新型的潜在结构类似物UAS03，它暴露了 与母体UROA化合物相比，抗炎和肠道屏障功能活动增加。这 当前的建议研究了UAS03的分子和细胞机制及其在其治疗效率中 IBD临床前模型。 我们的初步结果表明，UAS03的口服给药减轻了葡聚糖钠的结肠炎 硫酸盐（DSS） - 或2,4,6-三硝基苯磺酸（TNB）诱导的鼠结肠炎，即使在10倍下剂量下 与Uroa相比。 UAS03显着抑制了脂多糖（LPS）诱导的炎症增加 免疫细胞和上皮细胞中的介质比UROA高10倍。此外，处理 UAS03通过激活核因子通过上调连接蛋白来降低肠道通透性 （红细胞衍生的2） - 类似2（NRF2） - h-氧合酶（HO1）途径。基于这些结果，我们 提案UAS03和UROA的两种有益的有益活动，这些化合物可以保护宿主免受 通过保护肠道障碍功能和破坏炎症活动来面临外部挑战。在这个建议中，我们 将检验以下假设：“微生物代谢物的有效类似UAS03的处理”保护 通过减少屏障功能障碍和炎症来发展IBD。在AIM 1中，我们将调查如何 UROA/UROA通过上调连接蛋白作为NRF2依赖性的方式增加肠道屏障功能 以及分子事件涉及UAS03的抗炎活性。在AIM 2中，治疗效率 UAS03和UROA将在急性，慢性和赞助的IBD前临床模型中检查。在AIM 3中，我们 鉴定导致UROA产生的细菌并在结肠炎模型中测试其宝元活动的建议。 拟议研究的成功完成将允许了解UAS03和UROA机制 行动，并为IBD中的治疗用法建立基础。