Dietary Flavonoids-Microbiota-Ah Receptor Interactions in the Gut

肠道中膳食黄酮类化合物-微生物群-Ah 受体的相互作用

• 批准号: 9791345
• 负责人: Robert Stephen Chapkin
• 金额: $ 35.43万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791345
• 关键词: 3-Dimensional; Address; Anti-inflammatory; Aryl Hydrocarbon Receptor; Biological Assay; Biology; CYP1A1 gene; Cell Line; Cells; Chemicals; Chronic; Clinical Trials; Data; Diet; Dietary Flavonoid; Distal; Elements; Epithelial; Epithelial Cells; Epithelium; Flavonoids; Gastrointestinal tract structure; Genes; Goals; Health; Health Benefit; Health Promotion; Human; Immune; In Vitro; Individual; Inflammation; Inflammatory Response; Injury; Intestines; Knockout Mice; Laboratory Animals; Ligands; Link; Mediating; Metabolic; Metabolism; Modeling; Mucous Membrane; Mus; Natural regeneration; Nutrient; Organ; Organism; Organoids; Physiological; Play; Population; Production; Receptor Signaling; Regenerative response; Role; Signal Transduction; Source; Stem cells; Structure; Structure-Activity Relationship; Testing; Tumor-infiltrating immune cells; Wound Healing; antimicrobial; aryl hydrocarbon receptor ligand; base; experimental study; fruits and vegetables; gastrointestinal epithelium; gut microbiota; in vivo; interleukin-22; microbial; microbiome; microbiota; microorganism; multiple omics; novel; receptor-mediated signaling; regenerative; resilience; response; response to injury; three dimensional cell culture

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.

实验室动物研究和人体临床试验的大量证据表明，饮食