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

项目摘要 越来越多的证据表明，肠道微生物来源的代谢产物的膳食黄酮， 重要的是它们在结肠中的生物作用，如抗炎。然而，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的理解不足， 极大地限制了我们开发用于抑制结肠炎症的基于膳食类黄酮的策略的能力。 柑橘类水果及其成分的消费与炎症呈负相关- 与人类的慢性疾病有关。多甲氧基黄酮（PMFs），一类独特的柑橘类黄酮， 在我们的动物研究中显示出了有效的抗炎特性。我们找到了那条肠子 在口服PMF后，微生物群介导PMF的一系列结肠代谢物的产生 这些代谢产物的抗炎作用比它们的亲本强得多 PMF。重要的是，我们的研究结果表明，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，我们还发现了多种 PMF代谢细菌，并发现膳食PMF调节的丰度， 这些细菌在结肠炎小鼠中的代谢功能。总的来说，我们的研究结果为 柑橘PMF在预防结肠炎症和相关疾病中的应用。客观 本项目的主要目的是阐明PMFs与肠道菌群的相互作用模式及其意义 抑制结肠炎症根据我们的初步结果，我们假设肠道微生物群 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，我们将继续研究以下3个具体问题。 目的：1）鉴定结肠中PMF的新型微生物源性代谢产物并表征其组织 2）确定微生物来源的PMF代谢物在抑制结肠炎中的作用; 炎症;和3）表征PMF和PMF代谢粪便细菌之间的相互作用， 健康小鼠和结肠炎小鼠。我们的理由是，该项目的成功完成将 有助于开发有效的饮食策略以改善结肠炎症， 通过PMF/微生物群的相互作用来治疗相关疾病。

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.