. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics. Am J Physiol Gastrointest Liver Physiol 308: G1004-G1011, 2015. First published April 23, 2015; doi:10.1152/ajpgi.00002.2015.-Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P Ͻ 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 Ϯ 228.21 vs. 568.75 Ϯ 304.26 pg/ml, P ϭ 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r ϭ Ϫ0.39, P ϭ 0.03; urinary sucralose, r ϭ Ϫ0.47, P ϭ 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 Ϯ 409.56 vs. 6,818.02 Ϯ 628.78 ng/ml (P Ͻ 0.01) and 0.09 Ϯ 0.03 vs. 0.15 Ϯ 0.19 EU/ml (P Ͻ 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia.alcohol; lipopolysaccharide-binding protein; lipopolysaccharide ALCOHOL IS CONSUMED BY ABOUT one-half of the U.S. population and is the most frequently abused drug in the world (31). However, the most serious complication of heavy drinking, alcoholic liver disease (ALD), remains only partially understood. The amount and duration of alcohol consumed appear to be the most important risk factors for the development of ALD. About 20 -30% of individuals who consume over 30 g/day for 10 years go on to develop cirrhosis (46). However, there does not appear to be a clearly linear dose effect above this threshold, since certain groups of extremely heavy drinkers (Ͼ120 g/day) developed cirrhosis at a low rate (18.5%) (5). Therefore, epidemiological studies have shown that alcohol is a necessary cofactor to cause clinically significant ALD and cirrhosis, but other additional cofactors are required.The most well-supported pathogenesis of ALD is that alcohol increases intestinal permeability, which increases gutderived endotoxin, such as lipopolysaccharide (LPS), in the blood. This increase in gut-derived endotoxin initiates endotoxin-mediated hepatocellular dam...