Discovery and Biological Signatures of Microbiome-Derived Xanthohumol Metabolites and their Role in Ameliorating Inflammatory Bowel Disease

微生物组衍生的黄腐酚代谢物的发现和生物学特征及其在改善炎症性肠病中的作用

• 批准号: 10472280
• 负责人: Ryan D Bradley
• 金额: $ 2.71万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472280
• 关键词: 16S ribosomal RNA sequencing; 3-Dimensional; Abdominal Pain; Acids; Acute; Adrenal Cortex Hormones; Adult; Adverse effects; Affect; Anti-Inflammatory Agents; Antiinflammatory Effect; Bacteria; Basic Science; Binding; Biochemical; Biological; Blood; Body Weight decreased; Cells; Clinical Research; Clinical Trials; Coculture Techniques; Communities; Crohn' s disease; Data; Diagnosis; Diarrhea; Disease; Disease Marker; Disease remission; Etiology; Feces; Flare; Gastrointestinal tract structure; Goals; Hemorrhage; Human; Humulus; Immune response; Immunosuppressive Agents; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Knowledge; Label; Masks; Measurement; Measures; Metabolic; Metabolic Biotransformation; Metabolic Pathway; Methodology; Modality; Modeling; Monitor; Multiomic Data; Mus; Operative Surgical Procedures; Oral; Outcome; Parents; Participant; Pathologic; Pathway interactions; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Phenols; Placebos; Plasma; Predisposition; Proteins; Proteomics; Publishing; Randomized; Research Project Grants; Role; Severities; Statistical Computing; Surrogate Endpoint; System; Testing; Therapeutic; Time; Tube; Ulcerative Colitis; Urine; Variant; base; cytokine; design; dysbiosis; experimental study; fecal metabolome; gut microbes; gut microbiome; gut microbiota; improved; in vivo; inflammatory disease of the intestine; inflammatory marker; lipidome; metabolome; metabolomics; metagenomic sequencing; microbial; microbiome composition; microbiome signature; microbiota metabolites; novel therapeutics; prospective; stool sample; three dimensional cell culture; treatment choice

The limitations of current therapies for treatment of inflammatory bowel disease (IBD) underscore the need for new therapeutic modalities that both target the inflamed gut and the microbial dysbiosis causing the inflammation. Our published and preliminary data demonstrate that xanthohumol (XN), the principal prenylflavonoid found in hops (Humulus lupulus), exerts anti-inflammatory effects in vitro and in vivo by stimulating the anti-inflammatory Keap1-Nrf2 pathway while inhibiting the pro-inflammatory NFκB pathway. Furthermore, our studies show that mouse and human gut microbiota extensively metabolize XN and that the metabolites' bioactivities differ qualitatively and quantitatively from the parent XN. Overall, there is strong support for a mitigating impact of XN and its gut microbiota-derived metabolites on gut inflammation and IBD. We hypothesize that we can identify a biological signature of XN exposure and effect on IBD mitigation. Our corollary hypothesis is that specific gut microbiota alter the biological signature of XN exposure through metabolic transformations and that the resulting XN metabolites uniquely contribute to normalizing the IBD- associated microbial dysbiosis and inflammation. We define three specific aims: 1. Identify the interactions among XN, human gut microbiota species, and the inflamed intestine. Sub-aims: a) Identify gut microbiota-derived metabolites of XN in a fecal incubation system, b) Identify the molecular interactions of XN and its metabolites with gut microbial proteins at the species level by using activity-based proteomics, and c) Determine the anti-inflammatory and gut barrier-improving effects of XN and its metabolites in a 3D-cell culture model of the inflamed gut. 2. Identify biological signatures of longer-term oral treatment with XN in healthy and IBD subjects. We will conduct two prospective, randomized, triple-masked clinical trials, one with 24 adults diagnosed with IBD and one with 24 healthy control subjects. Participants will be randomized to either: 24 mg XN orally per day or daily placebo for 12 weeks. We will quantitatively determine established fecal and plasma markers of IBD, XN metabolite profiles, gut microbiome profiles, and fecal/plasma metabolome and lipidome profiles. 3. Generate a conceptual model for the understanding of the interactions between XN and the gut microbiome, and how the interactions benefit IBD mitigation. Based on computational integration of statistically processed multi-omics data from 16S rRNA gene sequencing, metagenome sequencing, metabolomics, and activity-based proteomics measurements, we will be able to predict which gut microbe species are responsible for which biotransformations of XN and its metabolites. The outcome of this aim will be a conceptual model of how these species interact at a community level to produce levels of XN and metabolites that ameliorate the dysbiosis and inflammation associated with IBD.

当前治疗炎症性肠病（IBD）治疗的局限 针对发炎的肠道和微生物营养不良的新型治疗方法，导致 炎。我们发表的初步数据表明，Xanthohumol（XN）是主要的 在啤酒花（Humulus lupulus）中发现的前氟氟氟氟氟化物，在体外和体内发挥抗炎作用 刺激抗炎的KEAP1-NRF2途径，同时抑制促炎性NFκB途径。 此外，我们的研究表明，小鼠和人类肠道微生物群广泛代谢XN，并且 代谢物的生物活性与父XN的定性和定量不同。总的来说，有强大的 支持XN及其肠道微生物核衍生的代谢产物对肠道注射和IBD的影响。 我们假设我们可以确定XN暴露的生物学特征以及对IBD缓解的影响。我们的 推论假设是特定的肠道菌群改变了XN暴露的生物学特征 代谢转化，所产生的Xn代谢产物独特地有助于使IBD- 相关的微生物营养不良和炎症。我们定义了三个具体目标： 1。确定XN，人肠道微生物群和发炎的肠之间的相互作用。子iams：a） 在粪便孵育系统中识别XN的肠道微生物源代谢物，b）识别分子 Xn及其代谢物与肠道微生物蛋白在物种水平上的相互作用，使用基于活动的相互作用 蛋白质组学以及c）确定XN及其ITS的抗炎和肠道屏障效应 在发炎的肠道3D细胞培养模型中的代谢产物。 2。确定健康和IBD受试者中XN长期口服治疗的生物学特征。我们将 进行两项前瞻性，随机，三重掩盖的临床试验，一项被诊断为24名成年人 一个有24个健康对照受试者。参与者将被随机分配到：每天24 mg XN 或每日安慰剂12周。我们将定量确定已建立的粪便和血浆标记 IBD，XN代谢产物谱，肠道微生物组轮廓以及粪便/等离子体代谢组和脂质谱图。 3。生成一个概念模型，以理解Xn和肠道微生物组之间的相互作用， 以及相互作用如何使IBD缓解措施受益。基于统计上的计算集成 来自16S rRNA基因测序，元基因组测序，代谢组学，代谢组学的多摩学数据 和基于活动的蛋白质组学测量值，我们将能够预测哪些肠道微生物物种是 负责XN及其代谢产物的生物转化。这个目标的结果将是 这些物种如何在社区层面相互作用以产生XN和 改善与IBD相关的营养不良和感染的代谢产物。