Swanson Garth R, Gorenz Annika, Shaikh Maliha, Desai Vishal, Forsyth Christopher, Fogg Louis, Burgess Helen J, Keshavarzian Ali
Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
Community, Systems and Mental Health Nursing, Rush University, Chicago, Illinois.
Am J Physiol Gastrointest Liver Physiol. 2015 Jun 15;308(12):G1004-11. doi: 10.1152/ajpgi.00002.2015. Epub 2015 Apr 23.
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 < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = -0.39, P = 0.03; urinary sucralose, r = -0.47, P = 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 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 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.
长期大量饮酒会导致肠道渗漏和酒精性肝病（ALD），但只有30%的酗酒者会出现肠道通透性增加和ALD。本研究的假设是，昼夜节律紊乱是积极饮酒的酗酒者发生肠道渗漏和内毒素血症的潜在危险因素。我们研究了20名酒精使用障碍（AD）患者和17名健康对照者（HC，6名日间工作者，11名夜间工作者）。受试者佩戴腕部活动记录仪7天，并接受24小时暗光期评估和尿液收集以检测肠道通透性。AD组的总睡眠时间明显减少，睡眠碎片化增加（P<0.05）。与HC相比，AD组的血浆褪黑素水平也显著降低[曲线下平均面积（AUC）322.78±228.21 vs. 568.75±304.26 pg/ml，P = 0.03]。在AD组中，褪黑素的AUC与小肠和结肠的肠道通透性呈负相关（乳果糖与甘露醇比值，r = -0.39，P = 0.03；尿蔗糖，r = -0.47，P = 0.01）。对HC和AD受试者进行24小时、每4小时一次的脂多糖结合蛋白（内毒素血症标志物）和脂多糖的余弦分析，其节律中线估计统计值分别为5,026.15±409.56 vs. 6,818.02±628.78 ng/ml（P<0.01）和0.09±0.03 vs. 0.15±0.19 EU/ml（P<0.05）。我们发现AD组的血浆褪黑素明显较低，而较低的褪黑素水平与肠道通透性增加和内毒素血症标志物相关。我们的研究表明，AD中褪黑素的抑制可能会促进肠道渗漏和内毒素血症。
