Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics

Abstract

. 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...

Utilizing melatonin to combat bacterial infections and septic injury

“…Moreover, peak concentrations of TNF‐α and IL‐6 were positively correlated with melatonin levels, suggesting that low melatonin availability alters circadian gene expression in the early stages of sepsis, leading to changes in pro‐inflammatory cytokine release (Li et al , ). Depressed melatonin levels induced by alcohol use disorders are correlated with elevated intestinal permeability, LPS‐binding protein (a marker of endotoxaemia) and LPS, showing that the suppression of melatonin may promote gut leakiness and endotoxaemia (Swanson et al , ). But these findings require confirmation (Kawada, ).…”

“…LPS administration and sepsis also induce fatigue and decreased contractility of the ileum, urinary bladder and diaphragm, which can be attenuated or even reversed and returned to control levels by melatonin administration (Paskaloglu et al , ; Kurcer et al , ). Reduced melatonin levels are associated with increased intestinal permeability (Swanson et al , ). In such cases, melatonin administration attenuates apoptotic cell death in both intestinal epithelium and lamina propria (Ozdemir et al , ) and prevents LPS‐induced gastrointestinal disturbances (De Filippis et al , ).…”

Risk factors associated with intestinal permeability in an adult population: A systematic review

“…Twenty‐four studies reported on 29 statistically significant biomarkers and association with altered IP . Two studies reported that fasting glucose had a weak positive correlation with IP (Table ).…”

“…Twenty-four studies reported on 29 statistically significant biomarkers and association with altered IP. 10,23,25,32,35,[40][41][42][43][44][50][51][52][53][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] Two studies reported that fasting glucose had a weak positive correlation with IP 44,53 (Table 5). Moreover, an additional study reported that a plasma glucose level >5.7 nmol/L is associated with a greater odds of having altered IP (OR = 2.09; 95% CI: 2.09, 4.18; P = 0.036) in the general population 23 (Table 3).…”

The Microbiota-gut-immune-glia (MGIG) Axis in Major Depression<strong> </strong>

“…Another negative aspect of kynurenine pathway activation is decreased conversion of tryptophan towards melatonin which besides its circadian rhythm regulating role, also has various immune-regulatory functions and has beneficial influence on intestinal permeability (157)(158)(159). Furthermore, it was demonstrated that increased intestinal LPS translocation in AIDS patients led to increased peripheral monocyte activation and increased trafficking into the brain, and it is believed that this mechanism contributes to HIV-associated dementia (160).…”