Circadian Desynchrony in Alcohol Induced Gut Leakiness

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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. PUBLIC HEALTH RELEVANCE: This study is a collaboration between scientists that study how alcohol damages the gut and scientists who study our body's natural rhythms (waking/sleeping, eating, etc.) called circadian rhythms. The proposed study uses human subjects to look for the first time at the relationships between circadian rhythms and alcohol consumption in the intestine. In this study we will answer two questions: 1) Does chronically drinking alcohol upset circadian rhythms (especially in the intestine) and thus result in intestinal injury that promotes disease? 2) Are patients who work nights at increased risk for damage in the intestine by acutely drinking alcohol (red wine). Answering these questions will result in a significant new understanding of the relationship between alcohol and circadian rhythms and could result in new preventative and therapeutic treatments for alcohol induced disease.