Dietary Flavonoids-Microbiota-Ah Receptor Interactions in the Gut

来自实验室动物研究和人类临床试验的大量证据表明，饮食 从水果和蔬菜中提取的黄酮类化合物可以预防肠道炎症 还能促进远端器官的健康。黄连保健作用的由来 单独的类黄酮类化合物及其混合物不仅与它们的直接作用有关，而且与 肠道微生物的代谢和肠道微生物种群的变化。 芳香烃受体(AhR)及其配体也起到保护性抗炎作用。 在肠子里。这项建议的总体假设是抗炎活性 黄酮类化合物的部分原因是它们作为AhR配体和它们的结构依赖的活性 与微生物群的相互作用。基于令人兴奋的显示结构的新的初步数据- 作为Cyp1A1和IL-22诱导剂的黄酮类化合物的依赖活性(一种关键的抗炎， 上皮再生反应基因)，AIMS 1a和b将表征结构依赖 利用结肠细胞和体外肠上皮模型研究黄酮类化合物对AhR信号的影响。目标 1C将通过调节AhR-IL-22来检测类黄酮抑制炎症的能力 免疫细胞群中的信号轴。AIM 2将使用多组学分析首先确定 黄酮类微生物代谢物的体外和体内互补分析(目标2a和b)， Aim 2c将使用一种新的计算方法来关联特定的类黄酮代谢物 以及它们的来源微生物。Aim 3a将研究AhR介导的黄酮类化合物的作用。 以及它们在结肠细胞系和有机3D培养物中的代谢产物。此外，目标3b 将研究黄酮类提取物在体内调节AhR介导的能力 对化学或遗传诱导的胃肠道粘膜损伤的再生、抗菌反应 特定的AhR KO小鼠。肠上皮特异性AhR KO与野生型的比较 对照小鼠，上皮与间质(含浸润性免疫细胞)的贡献 AHR介导的对粘膜损伤的再生反应将得到明确的确定。

There is extensive evidence from laboratory animal studies and human clinical trials that dietary flavonoids derived from fruits and vegetables protect against inflammation in the intestinal tract and also induce health benefits in distal organs. The genesis of the health-promoting effects of individual flavonoids and their mixtures has been linked not only to their direct effects but also to their metabolism by intestinal microbes and to their alteration of intestinal microbial populations. The aryl hydrocarbon receptor (AhR) and its ligands also play a protective anti-inflammatory role in the intestine. The overall hypothesis of this proposal is the anti-inflammatory activities of flavonoids are due, in part, to their structure-dependent activity as AhR ligands and their interactions with the microbiome. Based on exciting new preliminary data showing structure- dependent activity of flavonoids as inducers of Cyp1A1 and IL-22 (a key anti-inflammatory, epithelial regeneration response gene), Aims 1a&b will characterize the structure-dependent effects of flavonoids on AhR signaling using colonic cells and in vitro gut epithelial models. Aim 1c will examine the ability of flavonoids to suppress inflammation by modulating the AhR-IL-22 signaling axis in immune cell populations. Aim 2 will use multi-omic analytics to first identify microbial metabolites of flavonoids using complementary in vitro and in vivo assays (Aim 2a&b), and Aim 2c will use a novel computational approach to associate specific flavonoid metabolites with their source microorganisms. Aim 3a will examine the AhR-mediated effects of flavonoids and their metabolites in both the colonic cell lines and organoid 3d cultures. In addition, Aim 3b will investigate the in vivo ability of flavonoid extracts to modulate the AhR mediated regenerative, antimicrobial response to chemical or genetically induced mucosal injury in GI- specific AhR KO mice. By contrasting intestine epithelium-specific AhR KO with wild type control mice, the contribution of the epithelial vs stromal (containing infiltrating immune cells) AhR mediated regenerative response to mucosal injury will be definitively determined.