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
基本信息
- 批准号:10223195
- 负责人:
- 金额:$ 39.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-20 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnti-Inflammatory AgentsBacteriaBiologicalBiological AvailabilityBrassicaceaeCabbage - dietaryColitisColonComplexConsumptionDietDiseaseEngineeringEnvironmentEnvironmental Risk FactorFamilyFermentationFormulationGastroenterologyGlucosinolatesGlycosidesGoalsGrowthHealthHomeostasisHumanImmune responseIn VitroInflammationInflammatoryInflammatory Bowel DiseasesIsothiocyanatesKnowledgeLinkMediatingMetabolicMetabolismMicrobeModelingMolecular WeightMusNutrientOutcomePathway interactionsPatientsPhytochemicalPlantsProbioticsProductionRadishResearchResearch PersonnelRoleScientistSeveritiesSignal TransductionSiteSulforaphaneSupplementationSystems BiologyTechnologyTestingTherapeuticTissuesUlcerative ColitisValidationWorkbasecomputational platformcomputerized toolscruciferous vegetabledietaryfunctional foodgastrointestinal epitheliumglucoraphaningut microbiomegut microbiotahost microbiotahost-microbe interactionsin silicoin vivoinflammatory disease of the intestineinterestintestinal epitheliummembermetabolic profilemicrobialmicrobiotamouse modelmultiple omicspredictive testprograms
项目摘要
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.
这项提议利用了一支独特的调查团队,他们拥有互补的专业知识来圈定和利用
饮食、微生物区系和炎症性肠病之间的机制关系,从而建立
为许多感兴趣的生物特征绘制饮食-微生物区系-宿主相互作用的框架。我们会
设计并测试一种治疗溃疡性结肠炎的非传统联合生物疗法(营养素和微生物)
(UC),具有体内、体外和体内验证,并具有对合生素配方的通用性
治疗许多疾病。已经对肠道微生物区系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最终产物进行调节[3]。然而,几乎没有人
研究人员探索了肠道微生物区系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。在这些植物化学物质中有
硫代葡萄糖苷,低分子量S连接的糖苷存在于十字花科所有成员中(例如,
卷心菜、萝卜)[4]。硫代葡萄糖苷是微生物来源的异硫氰酸酯(ITCs)的前体代谢物,
作用于NF-κB和NRF2的抗炎药[5,6]。异硫氰酸酯的最佳合成依赖于
根据环境因素,包括由肠道微生物组建立的新陈代谢谱,尽管
机制还不太清楚[7]。利用计算工具和多组学方法,概述了
微生物介导的关键硫代葡萄糖苷(硫代萝卜素或GRN)转化为关键基因的知识差距
异硫氰酸酯(萝卜硫烷或SFN)为鉴定细菌物种提供了一个深刻的机会
最佳植物化学处理的能力、寄主反应和随后的有益于寄主的机制
健康。长期目标是通过以下途径最大限度地将异硫氰酸酯局部输送到炎症组织(S)
肠道微生物区系的操作和植物化学补充剂。建议进行这项研究的理由
一旦实现了对这些条件和物种的机械性理解,定制的合生体疗法
成为一种可能性。我们计划测试我们的中心假设,即特定的细菌对
通过将植物来源的硫代葡萄糖酸盐代谢成抗炎物质而引起的炎症性肠病
通过追求以下三个具体目标来实现异硫氰酸酯:(1)描述通过以下方式生产SFN的机制
已知的微生物物种。(2)利用体外培养的人结肠腺样体,检测三七总皂苷对肠上皮细胞的影响
动态平衡。(3)阐明部分合生元对SFN在小鼠结肠炎局部生物利用度的影响。
拟议的计划将由具有代谢建模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)以及活体小鼠
模特(科林博士、摩尔博士和罗森博士)。我们预计这项工作的完成将产生机械性的
以患者为中心联合治疗溃疡性结肠炎和其他肠炎性疾病的体会
为个性化的肠道环境量身定做的疾病。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Network analysis of toxin production in Clostridioides difficile identifies key metabolic dependencies.
- DOI:10.1371/journal.pcbi.1011076
- 发表时间:2023-04
- 期刊:
- 影响因子:4.3
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Jason Papin其他文献
Jason Papin的其他文献
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{{ truncateString('Jason Papin', 18)}}的其他基金
Systems biology approach to elucidate complex metabolic dependencies in the evolution of antibiotic resistance
系统生物学方法阐明抗生素耐药性进化中复杂的代谢依赖性
- 批准号:
10659296 - 财政年份:2023
- 资助金额:
$ 39.9万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 39.9万 - 项目类别:
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:
9788271 - 财政年份:2018
- 资助金额:
$ 39.9万 - 项目类别:
Mapping and predicting metabolic fluxes between the ileal microbiome and host
绘制和预测回肠微生物组和宿主之间的代谢通量
- 批准号:
8986799 - 财政年份:2014
- 资助金额:
$ 39.9万 - 项目类别:
Mapping and predicting metabolic fluxes between the ileal microbiome and host
绘制和预测回肠微生物组和宿主之间的代谢通量
- 批准号:
8791700 - 财政年份:2014
- 资助金额:
$ 39.9万 - 项目类别:
Mapping and predicting metabolic fluxes between the ileal microbiome and host
绘制和预测回肠微生物组和宿主之间的代谢通量
- 批准号:
9195132 - 财政年份:2014
- 资助金额:
$ 39.9万 - 项目类别:
Mapping and predicting metabolic fluxes between the ileal microbiome and host
绘制和预测回肠微生物组和宿主之间的代谢通量
- 批准号:
8605628 - 财政年份:2014
- 资助金额:
$ 39.9万 - 项目类别:
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