Characterization of Microbiota-derived Polymethoxyflavone Metabolites and their Anti-inflammatory Actions in the Colon

微生物群衍生的多甲氧基黄酮代谢物的表征及其在结肠中的抗炎作用

基本信息

批准号：
10229493
负责人：
Hang Xiao
金额：
$ 38.09万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
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

项目摘要

PROJECT SUMMARY Accumulating evidence suggested that gut microbiota-derived metabolites of dietary flavonoids are important for their biological actions in the colon such as anti-inflammation. However, currently, there is only a poor understanding of the formation and biofunctions of microbiota-derived flavonoid metabolites, which greatly limits our ability to develop dietary flavonoid-based strategies for inhibiting colonic inflammation. Consumption of citrus fruits and their components has been found to associate inversely with inflammation- related chronic diseases in humans. Polymethoxyflavones (PMFs), a unique class of citrus flavonoids, displayed potent anti-inflammatory properties in the colon in our animal studies. We found that gut microbiota mediated the production of an array of colonic metabolites of PMFs after their oral administration in mice, and these metabolites possessed much stronger anti-inflammatory effects than their parental PMFs. Importantly, our results showed that oral intake of PMFs by human volunteers resulted in the production of these bioactive metabolites in human stool. Furthermore, we identified multiple strains of PMF-metabolizing bacteria from human stool and found that dietary PMFs modulated the abundance and metabolic functions of these bacteria in mice with colitis. Overall, our results provided a strong basis for the application of citrus PMFs in the prevention of colonic inflammation and associated diseases. The objective of this project is to elucidate the mode of interaction between PMFs and gut microbiota, and its implication in inhibiting colonic inflammation. Based on our preliminary results, we hypothesize that gut microbiota mediates the production of bioactive PMF metabolites, and these metabolites are critical for the anti- inflammatory actions of PMFs in the colon. To test our hypothesis, we will pursue the following 3 specific aims: 1) Identify novel microbiota-derived metabolites of PMFs in the colon and characterize their tissue profiles in PMF-fed mice; 2) Determine the role of microbiota-derived PMF metabolites in inhibiting colonic inflammation; and 3) Characterize the interaction between PMFs and PMF-metabolizing fecal bacteria in both healthy mice and mice with colitis. Our rationale is that the successful completion of this project will contribute to the development of effective dietary strategies for amelioration of colonic inflammation and associated diseases through the PMF/microbiota interaction.

项目摘要积累的证据表明，饮食类黄酮的肠道微生物群代谢物是对于它们在结肠中的生物学作用至关重要，例如抗炎。但是，目前，只有对微生物源的类黄酮代谢产物的形成和生物调节的理解不足，这极大地限制了我们开发基于饮食类黄酮的策略来抑制结肠炎症的能力。发现柑橘类水果及其成分的消费与炎症成反比人类相关的慢性疾病。多甲氧基氟法酮（PMFS），一种独特的柑橘类黄酮，在我们的动物研究中，在结肠中显示出有效的抗炎特性。我们发现那肠微生物群介导了口服给药后的一系列PMF的结肠代谢产生在小鼠中，这些代谢产物具有比父母更强的抗炎作用 PMFS。重要的是，我们的结果表明，人类志愿者对PMF的摄入量导致在人粪便中产生这些生物活性代谢物。此外，我们确定了多种菌株人粪便中的PMF代谢细菌，发现饮食PMF调节了丰度和这些细菌在结肠炎小鼠中的代谢功能。总体而言，我们的结果为柑橘PMF在预防结肠炎症和相关疾病中的应用。目标这个项目的是阐明PMF和肠道菌群之间的相互作用及其含义在抑制结肠炎症中。根据我们的初步结果，我们假设肠道菌群介导生物活性PMF代谢产物的产生，这些代谢物对于抗 - PMF在结肠中的炎症作用。为了检验我们的假设，我们将追求以下3个特定的特定目的：1）鉴定结肠中PMF的新型微生物元素代谢物并表征其组织 PMF喂养的小鼠的剖面； 2）确定菌群衍生的PMF代谢产物在抑制结肠的作用炎; 3）表征PMFS与PMF-量代谢细菌之间的相互作用健康的小鼠和结肠炎小鼠。我们的理由是，该项目的成功完成将有助于制定有效的饮食策略，以改善结肠炎症和通过PMF/微生物群相互作用的相关疾病。