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 成年人患有代谢综合征并因此经历增加的心血管疾病风险， 2型糖尿病、炎症和感染。肥胖和/或相关疾病引起的直接医疗保健成本 疾病每年占美国所有卫生保健支出的7-10%。越来越多的证据表明 肥胖和代谢综合征中的肠道微生物群。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的 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 来自啤酒花植物的维生素D和黄腐酚介导先天免疫调节的机制 免疫力、改善肠道屏障功能、改变微生物群组成和减少肥胖症表现 和代谢综合征。我们的中心假设是黄腐酚和维生素D各自诱导表达 的抗菌肽（CAMP），并改善肠上皮屏障功能， 减少炎症，改变肠道微生物群的结构和功能， 超重/肥胖和代谢综合征。我们的基本原理是，一旦我们确定我们可以重复地操纵 微生物群的组成和功能与这两个代理，开发新的和创新的 预防和/或治疗肥胖症和相关疾病的方法是可能的。我们提出了三 具体目的：1）确定肠道微生物群对口服黄腐酚和/或维生素E的功效的贡献。 D治疗饮食诱导的肥胖症; 2）确定维生素D和/或黄腐酚 改变肠道微生物群组成/功能并减少饮食诱导的肥胖，以及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够阐明生物活性化合物，宿主因子， 肠道微生物组将整合，以影响炎症和 代谢紊乱影响数百万人的生命，并在全球范围内增加数十亿美元的医疗费用。

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.