Circadian Desynchrony in Alcohol Induced Gut Leakiness

描述（由申请人提供）：酒精性肝病（ALD）仅发生在一部分（30%）出现组织损伤和器官功能障碍的酗酒者中。这一公认的流行病学和临床观察表明，酒精滥用是必要的，但不足以造成组织损伤，还需要其他辅助因素。我们和其他人已经表明，增加肠通透性（肠漏）和内毒素血症是两个必要的辅助因素。关键问题是需要哪些额外的辅助因子来发展肠漏和内毒素血症。我们假设昼夜节律的改变是酒精引起的肠道渗漏和内毒素血症的重要决定因素。所有受试者都将接受以下测试：(1)昏暗光线下褪黑激素（DLMO）发生的时间和相位角的中心昼夜节律测试；(2)从口腔粘膜细胞测量的胃肠道外周昼夜节律基因表达测试。目的1：验证慢性酒精中毒患者存在昼夜节律紊乱的假设。我们将比较患有肠漏/内毒素血症的慢性酗酒者，并将他们与没有肠漏/内毒素血症的对照组进行比较。我们假设，有肠道渗漏的酗酒者比没有肠道渗漏的对照组有更大的中枢和/或外周昼夜节律紊乱。目的2：验证轮班工人昼夜节律紊乱增加酒精诱发肠道渗漏的假设。对不饮酒的轮班工人和白班工人进行为期一周的适度饮酒前后（每天0.4 g ETOH/kg）的前瞻性研究。我们假设轮班工人比白天工作的对照组更容易受到酒精引起的肠道渗漏的影响。这项研究将揭示酒精和昼夜生物学在ALD发病机制中的相互作用的重要新信息，可用于改善ALD的预防和治疗。

DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) occurs only in a subset of alcoholics ( 30%) that develop tissue injury and organ dysfunction. This well established epidemiological and clinical observation indicates that alcohol abuse is required but not sufficient to cause tissue injury and additional cofactors are required. We and other have shown that increased intestinal permeability (gut leakiness) and endotoxemia are two required cofactors. The key question is what additional cofactors are needed to develop gut leakiness and endotoxemia. We hypothesize that altered circadian rhythms are an important determinant in alcohol induced gut leakiness and endotoxemia. All subjects will undergo testing for (1) central circadian rhythm from the timing and phase angle of the dim light melatonin onset (DLMO) and (2) peripheral circadian clock gene expression in the gastrointestinal tract measured from buccal mucosal cells. Aim 1: To test the hypothesis that circadian disruption is present in chronic alcoholics with gut leakiness. We will compare chronic alcoholics with gut leakiness/endotoxemia and compare them to matched alcoholic controls without gut leakiness/endotoxemia. We hypothesize that alcoholics with gut leakiness will have greater central and/or peripheral circadian disruption than matched alcoholic controls without leakiness. Aim 2: To test the hypothesis that circadian disruption in shift workers increases susceptibility to alcohol induced gut leakiness. Non alcoholic shift workers and daytime workers will be prospectively studied before and after moderate alcohol consumption for one week (0.4 g ETOH/kg per day). We hypothesize that shift workers will be more susceptible to alcohol induced gut leakiness than the matched controls on a daytime work schedule. This study will reveal significant new information regarding the interaction of alcohol and circadian biology in ALD pathogenesis that could be used to improve prevention and treatment of ALD.