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

基本信息

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
项目类别：
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

项目摘要

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.

目前治疗炎症性肠病（IBD）的疗法的局限性凸显了对以下药物的需求：新的治疗方式既针对发炎的肠道，也针对导致肠道菌群失调的微生物失调我们发表的初步数据表明，黄腐酚 (XN) 是主要的炎症。啤酒花（啤酒花）中发现的异戊二烯类黄酮，通过以下方式在体外和体内发挥抗炎作用：刺激抗炎 Keap1-Nrf2 通路，同时抑制促炎 NFκB 通路。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在质量和数量上与母体 XN 总体上存在很大差异。支持 XN 及其肠道微生物衍生代谢物对肠道炎症和 IBD 的影响。我们探索了可以识别 XN 暴露的生物特征以及对 IBD 缓解的影响。推论假设是，特定的肠道微生物群通过以下方式改变 XN 暴露的生物特征：代谢转化以及由此产生的 XN 代谢物独特地有助于 IBD-正常化相关的微生物失调和炎症。我们定义了三个具体目标： 1. 确定 XN、人类肠道微生物群和发炎肠道之间的相互作用：a) 在粪便培养系统中鉴定肠道微生物群衍生的 XN 代谢物，b) 鉴定分子通过使用基于活性的方法，在物种水平上 XN 及其代谢物与肠道微生物蛋白的相互作用蛋白质组学，c) 确定 XN 及其抗炎和改善肠道屏障的作用发炎肠道 3D 细胞培养模型中的代谢物。 2. 确定健康和 IBD 受试者长期口服 XN 治疗的生物学特征。进行两项前瞻性、随机、三重屏蔽临床试验，其中一项有 24 名被诊断患有 IBD 的成年人一项有 24 名健康对照受试者，参与者将被随机分配到以下任一组：每天口服 24 毫克 XN。或每天服用安慰剂，持续 12 周，我们将定量测定已建立的粪便和血浆标记物。 IBD、XN 代谢物概况、肠道微生物组概况以及粪便/血浆代谢组和脂质组概况。 3. 生成一个概念模型来理解 XN 和肠道微生物组之间的相互作用，以及基于记者的计算整合，交互如何有利于 IBD 缓解。处理来自 16S rRNA 基因测序、宏基因组测序、代谢组学的多组学数据，和基于活性的蛋白质组学测量，我们将能够预测哪些肠道微生物种类负责 XN 及其代谢物的生物转化该目标的结果将是这些物种如何在群落层面相互作用以产生 XN 水平的概念模型改善与 IBD 相关的生态失调和炎症的代谢物。