Systems biology of microbe-mediated glucosinolate bioconversion in inflammatory bowel disease

炎症性肠病微生物介导的芥子油苷生物转化的系统生物学

• 批准号: 10179960
• 负责人: Jason Papin
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179960
• 关键词: Affect; Anti-Inflammatory Agents; Bacteria; Biological; Biological Availability; Brassicaceae; Cabbage - dietary; Colitis; Colon; Complex; Consumption; Diet; Disease; Engineering; Environment; Environmental Risk Factor; Family; Fermentation; Formulation; Gastroenterology; Glucosinolates; Glycosides; Goals; Growth; Health; Homeostasis; Human; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Isothiocyanates; Knowledge; Link; Mediating; Metabolic; Metabolism; Microbe; Modeling; Molecular Weight; Mus; Nutrient; Outcome; Pathway interactions; Patients; Phytochemical; Plants; Probiotics; Production; Radish; Research; Research Personnel; Role; Scientist; Severities; Signal Transduction; Site; Sulforaphane; Supplementation; Systems Biology; Technology; Testing; Therapeutic; Tissues; Ulcerative Colitis; Validation; Work; base; computational platform; computerized tools; cruciferous vegetable; functional food; gastrointestinal epithelium; glucoraphanin; gut microbiome; gut microbiota; host microbiota; host-microbe interactions; in silico; in vivo; inflammatory disease of the intestine; interest; intestinal epithelium; member; metabolic profile; microbial; microbiota; mouse model; multiple omics; predictive test; programs

This proposal capitalizes on a unique team of investigators with complementary expertise to delineate and exploit the mechanistic relationships between diet, the microbiota, and inflammatory bowel disease and thus establish a framework for mapping diet-microbiota-host interactions for many biological signatures of interest. We will engineer and test an unconventional synbiotic therapy (nutrients plus microbes) for treating ulcerative colitis (UC), with in silico, ex vivo, and in vivo validation and approaches with generalizability to synbiotic formulations for many diseases. Extensive research has been performed on the anti-inflammatory role of the gut microbiota, primarily mediated through endogenous microbial molecules and fermentation end products [3]. However, few investigators have explored the capacity of the gut microbiota to metabolize bioactive molecules, specifically plant-derived dietary metabolites that ameliorate gut inflammation. Among these phytochemicals are glucosinolates, low molecular weight S-linked glycosides present in all members of the Brassicaceae family (e.g., cabbage, radishes) [4]. Glucosinolates are precursor metabolites for microbe-derived isothiocyanates (ITCs), anti-inflammatory agents that act on NF-κB and Nrf2 [5,6]. Optimal synthesis of isothiocyanates is dependent upon environmental factors that include a metabolic profile established by the gut microbiome although the mechanisms are poorly understood [7]. Using computational tools and multi-omic approaches, the outlined knowledge gap of microbe-mediated conversion of a key glucosinolate (glucoraphanin or GRN) to a key isothiocyanate (sulforaphane or SFN) presents a profound opportunity to identify bacterial species with defined capacity for optimal phytochemical processing, host responses, and subsequent mechanisms of benefit to host health. The long-term goal is to maximize localized delivery of isothiocyanates to inflamed tissue(s) through manipulation of the gut microbiota and phytochemical supplementation. The rationale for the proposed research is that once a mechanistic understanding of these conditions and species is achieved, tailored synbiotic therapies become a possibility. We plan to test our central hypothesis that specific bacteria have a mitigating effect on inflammatory bowel disease by metabolizing a plant-derived glucosinolate into an anti-inflammatory isothiocyanate by pursuing the following three specific aims: (1) Delineate mechanisms of SFN production by known microbial species. (2) Employ ex vivo human colonoids to test the impact of SFN on intestinal epithelial homeostasis. (3) Elucidate the impact of selected synbiotics on localized SFN bioavailability in murine colitis. The proposed program will be implemented by investigators with expertise in metabolic modeling and omics technologies (Dr. Papin), enteroid models and gastroenterology (Drs. Moore and Rosen), and in vivo mouse models (Drs. Kolling, Moore, and Rosen). We anticipate that completion of this work will generate mechanistic understanding of patient-centric synbiotic therapies for ulcerative colitis and other intestinal inflammatory disorders tailored to the individualized gut environment.

该提案利用了一个独特的研究人员团队，他们具有互补的专业知识来描述和利用 饮食、微生物群和炎症性肠病之间的机制关系，从而建立 用于绘制许多感兴趣的生物特征的饮食-微生物-宿主相互作用的框架。我们将 设计并测试治疗溃疡性结肠炎的非常规合生疗法（营养素加微生物） (UC)，通过计算机、离体和体内验证以及可推广到合生元制剂的方法 对于许多疾病。人们对肠道微生物群的抗炎作用进行了广泛的研究， 主要通过内源微生物分子和发酵终产物介导[3]。然而，很少有 研究人员探索了肠道微生物群代谢生物活性分子的能力，特别是 植物来源的饮食代谢物可改善肠道炎症。这些植物化学物质包括 芥子油苷，低分子量 S 连接糖苷，存在于十字花科所有成员中（例如， 卷心菜、萝卜）[4]。芥子油苷是微生物衍生的异硫氰酸盐 (ITC) 的前体代谢物， 作用于 NF-κB 和 Nrf2 的抗炎剂 [5,6]。异硫氰酸酯的最佳合成取决于 取决于环境因素，包括肠道微生物组建立的代谢特征，尽管 机制尚不清楚[7]。使用计算工具和多组学方法，概述了 微生物介导的关键芥子油苷（萝卜硫苷或GRN）转化为关键物质的知识差距 异硫氰酸盐（萝卜硫素或 SFN）为识别具有明确定义的细菌物种提供了深刻的机会 最佳植物化学处理、宿主反应以及随后对宿主有益的机制的能力 健康。长期目标是通过以下方式最大限度地向发炎组织局部输送异硫氰酸盐： 控制肠道微生物群和补充植物化学物质。拟议研究的理由 一旦对这些条件和物种有了机械性的了解，量身定制的合生疗法 成为一种可能性。我们计划检验我们的中心假设，即特定细菌对 通过将植物来源的芥子油苷代谢为抗炎物质来治疗炎症性肠病 异硫氰酸盐通过追求以下三个具体目标：（1）描述SFN生产的机制 已知的微生物种类。 (2)采用离体人体结肠来测试SFN对肠上皮的影响 体内平衡。 (3) 阐明所选合生元对小鼠结肠炎局部 SFN 生物利用度的影响。 拟议的计划将由具有代谢模型和组学专业知识的研究人员实施 技术（Papin 博士）、肠样模型和胃肠病学（Moore 和 Rosen 博士）以及体内小鼠 模型（Kolling 博士、Moore 博士和 Rosen 博士）。我们预计这项工作的完成将产生机械 了解以患者为中心的溃疡性结肠炎和其他肠道炎症的合生疗法 针对个体化肠道环境的疾病。