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

项目总结 越来越多的证据表明，肠道微生物区系衍生的膳食类黄酮代谢产物是 对它们在结肠中的生物学作用很重要，如抗炎。但是，目前只有 对微生物衍生的类黄酮代谢物的形成和生物功能认识不足 极大地限制了我们开发基于饮食类黄酮的抑制结肠炎的策略的能力。 研究发现，食用柑橘类水果及其成分与炎症成反比。 人类相关的慢性疾病。多甲氧基黄酮(PMF)是一类独特的柑橘类黄酮类化合物。 在我们的动物研究中，它在结肠中显示出强大的抗炎特性。我们找到了那根肠子 微生物区系介导PMF口服后一系列结肠代谢物的产生 在小鼠体内，这些代谢物具有比它们的亲本更强的抗炎作用 PMF。重要的是，我们的结果表明，人类志愿者口服PMF会导致 这些生物活性代谢物在人类粪便中的产生。此外，我们还鉴定了多个菌株。 人类粪便中PMF代谢细菌的研究发现，饮食PMF调节了PMF的丰度和 这些细菌在结肠炎小鼠体内的代谢功能。总体而言，我们的结果为 柑橘PMF在预防结肠炎及相关疾病中的应用。目标是 本项目的目的是阐明PMF与肠道微生物区系之间的相互作用模式及其意义 在抑制结肠炎方面。根据我们的初步结果，我们假设肠道微生物区系 介导生物活性PMF代谢物的产生，这些代谢物对于抗 PMF在结肠中的炎症作用。为了验证我们的假设，我们将探讨以下3个具体问题 目的：1)确定PMF在结肠中的新的微生物区系代谢物，并表征其组织特征 PMF喂养的小鼠的分布；2)确定微生物来源的PMF代谢物在抑制结肠中的作用 炎症；以及3)表征PMF和PMF代谢粪便细菌之间的相互作用 无论是健康的小鼠还是结肠炎的小鼠。我们的理由是，这个项目的成功完成将 有助于制定有效的饮食策略，以改善结肠炎和 通过PMF/微生物区系相互作用导致的相关疾病。

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.