Dietary Flavonoids-Microbiota-Ah Receptor Interactions in the Gut

实验室动物研究和人类临床试验中有大量证据表明， 从水果和蔬菜中提取的黄酮类化合物可以防止肠道炎症 并且还在远端器官中引起健康益处。的健康促进作用的起源 单独的黄酮类化合物及其混合物不仅与它们的直接作用有关， 它们通过肠道微生物的代谢以及它们改变肠道微生物种群。 芳香烃受体（AhR）及其配体也发挥保护性抗炎作用 在肠道里。该建议的总体假设是， 黄酮类化合物是由于，部分，它们的结构依赖性活性作为AhR配体和它们的 与微生物的相互作用。基于令人兴奋的新的初步数据显示结构- 类黄酮作为Cyp 1A 1和IL-22（一种关键的抗炎， 上皮再生反应基因），目的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黄酮类化合物对AhR信号传导的影响。目的 图1c将检查类黄酮通过调节AhR-IL-22来抑制炎症的能力。 免疫细胞群中的信号轴。Aim 2将使用多组学分析首先识别 使用互补的体外和体内测定法（Aim 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 与它们的来源微生物。目的3a将检查类黄酮的AhR介导的作用 以及它们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 对化学或遗传诱导的胃肠道粘膜损伤的再生、抗菌反应， 特异性AhR KO小鼠。通过对比肠上皮特异性AhR KO与野生型 对照小鼠，上皮细胞与间质细胞（含有浸润性免疫细胞）的贡献 将明确确定AhR介导的对粘膜损伤的再生反应。

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.