Vitamin D, Xanthohumol and Nuclear Receptors: Targeting Immunity, Microbiota and

我们面临着由肥胖和代谢综合征流行引发的全球健康危机。超过34%的美国人 成年人患有代谢综合征，因此患心血管疾病的风险增加， 2型糖尿病、炎症和感染。肥胖和/或与肥胖相关的直接医疗费用 疾病每年占美国医疗保健总支出的7%-10%。越来越多的证据表明 肥胖和代谢综合征的肠道微生物区系。我们的长期目标是发现天然化合物 它可以调节免疫功能，并利用这些知识开发具有成本效益 补充治疗以改善人类健康。我们在这个项目中的目标是确定 啤酒花植物中的维生素D和黄腐酚调节内源激素的机制 免疫，改善肠道屏障功能，改变微生物区系组成，减少肥胖表现 和代谢综合症。我们的中心假设是黄腐酚和维生素D各自诱导表达 中草药抗菌肽(CAMP)在黏膜上皮细胞中的表达，并改善肠上皮屏障功能， 减少炎症，改变肠道微生物区系的结构和功能，最终减少 超重/肥胖和Met。我们的理论基础是，一旦我们确定我们可以重复地操纵 微生物区系的组成和功能与这两种菌剂的结合，开发了新的和创新的 预防和/或治疗肥胖症和相关疾病的方法是可能的。我们提出三个建议 具体目标：1)确定肠道微生物区系对口服黄腐酚和/或维生素疗效的贡献 D治疗饮食引起的肥胖；2)确定维生素D和/或黄腐酚的机制 改变肠道微生物区系组成/功能，减少饮食诱导的肥胖；3)确定 维生素D和/或黄腐酚改善肠道屏障防御并降低肥胖小鼠对 感染。我们希望这项研究能阐明生物活性化合物、宿主因子、 肠道微生物群的整合将影响炎症性和非炎症性疾病的补充治疗效果。 代谢紊乱影响数百万人的生活，并在全球范围内增加数十亿美元的医疗成本。

We face a global health crisis sparked by an epidemic in obesity and metabolic syndrome. Over 34% of US adults suffer from metabolic syndrome and therefore experience increased risk for cardiovascular disease, type 2 diabetes, inflammation and infection. Direct health care costs arising from obesity and/or related disorders account for 7-10% of all US health care expenditures annually. Mounting evidence has implicated the gut microbiota in obesity and metabolic syndrome. Our long-term goal is to discover natural compounds that can modulate immune function and capitalize on that knowledge to develop cost-effective complementary treatments to improve human health. Our objectives in this project are to determine mechanisms by which vitamin D and xanthohumol from the hops plant mediate regulation of innate immunity, improve gut barrier function, alter microbiota composition and reduce manifestations of obesity and metabolic syndrome. Our central hypothesis is that xanthohumol and vitamin D each induce expression of cathelicidin antimicrobial peptide (CAMP) in mucosal epithelia and improve gut epithelial barrier function, reduce inflammation, modify the structure and function of the gut microbiota, and ultimately reduce overweight/obesity and MetS. Our rationale is that, once we establish that we can reproducibly manipulate the composition and function of the microbiota with these two agents, development of new and innovative approaches to prevent and/or treat obesity and related disorders would be possible. We propose three Specific Aims: 1) determine the contribution of gut microbiota to efficacy of oral xanthohumol and/or vitamin D treatment of diet-induced obesity; 2) determine the mechanism by which vitamin D and/or xanthohumol alter the gut microbiota composition/function and reduce diet induced obesity and 3) determine efficacy of vitamin D and/or xanthohumol to improve gut barrier defense and reduce susceptibility of obese mice to infection. We expect this study to elucidate how interactions between bioactive compounds, host factors, and the gut microbiome will integrate to impact the effect of complementary treatment for inflammatory and metabolic disorders that impact millions of lives and add billions of dollars to healthcare costs worldwide.