Diurnal variations in intestinal barrier integrity and liver pathology in mice: implications for alcohol binge

Abstract

Recent studies suggest that circadian rhythms regulate intestinal barrier integrity, but it is not clear whether there are daily variations in barrier integrity. This study investigated daily variations in intestinal barrier integrity, including whether there are differences in alcohol-induced intestinal barrier dysfunction after an alcohol binge at different times of day and whether this is associated with concurrent liver injury. C57BL6/J male mice were fed a standard chow diet, an alcohol-containing liquid diet, or an alcohol control diet for 4 wk. During week 5 (i.e., on days 43-45), mice received three once-daily gavages of alcohol (6 g/kg) or the control (phosphate-buffered saline) at the same time each day. Immediately after the binge on the second day, intestinal permeability was assessed. Four hours after the third and final binge, mice were euthanized and tissue samples collected. The results demonstrated diet-specific and outcome-specific effects of time, alcohol, and/or time by alcohol interaction. Specifically, the alcohol binge robustly influenced markers of intestinal barrier integrity, and liver markers were robustly influenced by time of day. Only intestinal permeability (i.e., sucralose) demonstrated a significant effect of time and also showed a binge by time interaction, suggesting that the time of the alcohol binge influences colonic permeability. NEW & NOTEWORTHY This study investigated daily variations in intestinal barrier integrity, including whether there are differences in alcohol-induced intestinal barrier dysfunction after an alcohol binge at different times of day and whether this is associated with concurrent liver injury. We conclude that 1) alcohol binge significantly impacted markers of intestinal permeability, 2) time of day significantly affected liver outcomes, and 3) the time of day influenced colonic permeability.

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

“…22 Mice with binge alcohol drinking at ZT12 had higher serum alcohol levels than ZT0, and serum LPS levels were highest when gavage was performed at ZT4 or ZT8. 22 Exposure of zebrafish larvae to 5% ethanol for 1 hour can be fatal, and a previous study found that mortality was highest with exposure at ZT2 and lowest at ZT18, indicating the time-dependent effects of alcohol. 23 Mice with albumin promoter-driven Cre recombinase (Alb-Cre mice) have Cre expression selectively in hepatocytes and hepatic stellate cells (HSCs).…”

“…Alcohol drinking may cause different effects depending on the time of drinking, and binge alcohol gavage in different ZT showed different effects in mice . Mice with binge alcohol drinking at ZT12 had higher serum alcohol levels than ZT0, and serum LPS levels were highest when gavage was performed at ZT4 or ZT8 . Exposure of zebrafish larvae to 5% ethanol for 1 hour can be fatal, and a previous study found that mortality was highest with exposure at ZT2 and lowest at ZT18, indicating the time‐dependent effects of alcohol .…”

“…ZT0 indicates the start of the light phase, and ZT12 indicates the start of the dark phase. Alcohol drinking may cause different effects depending on the time of drinking, and binge alcohol gavage in different ZT showed different effects in mice . Mice with binge alcohol drinking at ZT12 had higher serum alcohol levels than ZT0, and serum LPS levels were highest when gavage was performed at ZT4 or ZT8 .…”

Alcohol Effects on Colon Epithelium are Time‐Dependent

“…The tissue harvest was conducted 4 hours after the third and final binge. In this protocol, the serum alcohol level at the sacrifice was not affected by time, with the mean serum alcohol level per ZT not exceeding 1 mM (Voigt et al., ).…”

Alcohol-Induced Immune Dysregulation in the Colon Is Diurnally Variable

“…The animals were euthanized by conscious decapitation 4 h after the third gavage on day 45. Using this protocol, it has been shown that serum alcohol level at sacrifice is not affected by time, with mean serum alcohol level per ZT not exceeding 1 mM [22]. Proximal colon was collected every 4 h/cohort across the diurnal cycle, starting at ZT0.…”