Dietary Flavonoids-Microbiota-Ah Receptor Interactions in the Gut

实验室动物研究和人体临床试验有大量证据表明饮食 来自水果和蔬菜的类黄酮可预防肠道炎症 并且还对远端器官产生健康益处。促进健康作用的起源 单个黄酮类化合物及其混合物不仅与其直接作用有关，而且还与 它们通过肠道微生物的代谢及其对肠道微生物种群的改变。 芳烃受体（AhR）及其配体也发挥保护性抗炎作用 在肠道里。该提案的总体假设是抗炎活性 黄酮类化合物的部分原因在于它们作为 AhR 配体的结构依赖性活性及其 与微生物组的相互作用。基于显示结构的令人兴奋的新初步数据- 类黄酮作为 Cyp1A1 和 IL-22（一种关键的抗炎、 上皮再生反应基因），目标 1a 和 b 将表征结构依赖性 使用结肠细胞和体外肠上皮模型研究类黄酮对 AhR 信号传导的影响。目标 1c 将检查类黄酮通过调节 AhR-IL-22 抑制炎症的能力 免疫细胞群中的信号轴。目标 2 将使用多组学分析来首先识别 使用互补的体外和体内测定（目标 2a 和 b）研究黄酮类化合物的微生物代谢物， Aim 2c 将使用一种新颖的计算方法来关联特定的类黄酮代谢物 及其来源微生物。目标 3a 将检查类黄酮的 AhR 介导作用 及其在结肠细胞系和类器官 3d 培养物中的代谢物。此外，目标 3b 将研究类黄酮提取物在体内调节 AhR 介导的能力 对胃肠道中化学或遗传引起的粘膜损伤的再生、抗菌反应 特定的 AhR KO 小鼠。通过将肠上皮特异性 AhR KO 与野生型进行对比 对照小鼠，上皮细胞与基质细胞（含有浸润免疫细胞）的贡献 AhR 介导的粘膜损伤再生反应将得到明确确定。

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.