Night workers with circadian misalignment are susceptible to alcohol-induced intestinal hyperpermeability with social drinking

Abstract

Alcohol-induced intestinal hyperpermeability (AIHP) is a known risk factor for alcoholic liver disease (ALD), but only 20-30% of heavy alcoholics develop AIHP and ALD. The hypothesis of this study is that circadian misalignment would promote AIHP. We studied two groups of healthy subjects on a stable work schedule for 3 mo [day workers (DW) and night workers (NW)]. Subjects underwent two circadian phase assessments with sugar challenge to access intestinal permeability between which they drank 0.5 g/kg alcohol daily for 7 days. Sleep architecture by actigraphy did not differ at baseline or after alcohol between either group. After alcohol, the dim light melatonin onset (DLMO) in the DW group did not change significantly, but in the NW group there was a significant 2-h phase delay. Both the NW and DW groups had no change in small bowel permeability with alcohol, but only in the NW group was there an increase in colonic and whole gut permeability. A lower area under the curve of melatonin inversely correlated with increased colonic permeability. Alcohol also altered peripheral clock gene amplitude of peripheral blood mononuclear cells in CLOCK, BMAL, PER1, CRY1, and CRY2 in both groups, and inflammatory markers lipopolysaccharide-binding protein, LPS, and IL-6 had an elevated mesor at baseline in NW vs. DW and became arrhythmic with alcohol consumption. Together, our data suggest that central circadian misalignment is a previously unappreciated risk factor for AIHP and that night workers may be at increased risk for developing liver injury with alcohol consumption.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…In a following week, all subjects were given red wine (0.5 g of ethanol per kg body weight) every day after finishing work and before bedtime for 1 week . Blood samples were collected with same procedures to baseline samples (postalcohol samples) . This study has demonstrated that nighttime workers but not daytime workers have delayed melatonin secretion peak after 1 week alcohol period, and alcohol consumption increases gut permeability only in nighttime workers, suggesting that nighttime workers are more susceptible for alcohol drinking than daytime workers .…”

“…A previous study has analyzed the effects of moderate alcohol drinking on circadian rhythms using 11 daytime workers and 11 nighttime workers. In this study, all subjects were told to avoid alcohol drinking and have usual sleep schedule for 1 week . After an alcohol‐free week, subjects were kept in dim light, blood samples were collected, and serum melatonin levels were analyzed in every hour for 24 hours (baseline samples) .…”

“…In this study, all subjects were told to avoid alcohol drinking and have usual sleep schedule for 1 week . After an alcohol‐free week, subjects were kept in dim light, blood samples were collected, and serum melatonin levels were analyzed in every hour for 24 hours (baseline samples) . In a following week, all subjects were given red wine (0.5 g of ethanol per kg body weight) every day after finishing work and before bedtime for 1 week .…”

Circadian Rhythms in Gastrointestinal Health and Diseases

“…This suggests that circadian disruption contributes to IHP and a pro-inflammatory state, due, at least in part, to perturbed relationships between intestinal microbiota and intestinal gene expression. Dr. Swanson presented a recent human study on the effects of circadian disruption on alcohol-induced IHP (AIHP) comparing night-shift to day-shift workers for response to small doses of alcohol (0.5g/kg=2 glasses of wine/day for 7 days) 9 . Night-workers had increased AIHP, which was correlated with 24-hour area under the curve (AUC) of serum melatonin, a measure of central circadian alignment.…”

Summary of the 2017 Alcohol and Immunology Research Interest Group (AIRIG) meeting

“…Further, transplantation of stool from patients with alcoholic hepatitis into alcohol-fed mice caused severe ASH compared to stool transplantation from control subjects (Llopis et al, 2016). Recent data from Keshavarian’s lab suggest that disruption of circadian rhythms promotes alcohol-induced dysbiosis and gut leakiness (Summa et al, 2013; Swanson et al, 2016; Voigt et al, 2014), and could therefore be a susceptibility factor for alcohol-induced, gut-derived inflammation. Disrupted circadian rhythms are common in western societies, affecting at least 30% of the population through shift work and social jet lag (Roenneberg, Allebrandt, Merrow, & Vetter, 2012; Zelinski, Deibel, & McDonald, 2014), which intriguingly correlates to that fact that 30% of alcoholics develop dysbiosis, gut leakiness, and clinically relevant organ damage (Gao & Bataller, 2011).…”