title: Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics.
abstract: 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.
authors.affiliation: Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois; garth_swanson@rush.edu.
authors.forename: Garth R
authors.initials: GR
authors.lastname: Swanson
authors.affiliation: Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
authors.forename: Annika
authors.initials: A
authors.lastname: Gorenz
authors.affiliation: Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
authors.forename: Maliha
authors.initials: M
authors.lastname: Shaikh
authors.affiliation: Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
authors.forename: Vishal
authors.initials: V
authors.lastname: Desai
authors.affiliation: Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
authors.forename: Christopher
authors.initials: C
authors.lastname: Forsyth
authors.affiliation: Community, Systems and Mental Health Nursing, Rush University, Chicago, Illinois.
authors.forename: Louis
authors.initials: L
authors.lastname: Fogg
authors.affiliation: Departments of Behavioral Sciences and Internal Medicine, Rush University Medical Center, Chicago, Illinois;
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Burgess
authors.affiliation: Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois; Departments of Pharmacology, Molecular Biophysics & Physiology, Rush University Medical Center, Chicago, Illinois; and.
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002940:Circadian Rhythm / Q000502:physiology; D019446:Endotoxemia / Q000209:etiology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008108:Liver Diseases, Alcoholic / Q000150:complications*; D008297:Male; D008550:Melatonin / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D012890:Sleep / Q000502:physiology; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008550:Melatonin; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein
keywords: alcohol; lipopolysaccharide; lipopolysaccharide-binding protein