Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation

Abstract

The circadian clock orchestrates temporal patterns of physiology and behavior relative to the environmental light:dark cycle by generating and organizing transcriptional and biochemical rhythms in cells and tissues throughout the body. Circadian clock genes have been shown to regulate the physiology and function of the gastrointestinal tract. Disruption of the intestinal epithelial barrier enables the translocation of proinflammatory bacterial products, such as endotoxin, across the intestinal wall and into systemic circulation; a process that has been linked to pathologic inflammatory states associated with metabolic, hepatic, cardiovascular and neurodegenerative diseases – many of which are commonly reported in shift workers. Here we report, for the first time, that circadian disorganization, using independent genetic and environmental strategies, increases permeability of the intestinal epithelial barrier (i.e., gut leakiness) in mice. Utilizing chronic alcohol consumption as a well-established model of induced intestinal hyperpermeability, we also found that both genetic and environmental circadian disruption promote alcohol-induced gut leakiness, endotoxemia and steatohepatitis, possibly through a mechanism involving the tight junction protein occludin. Circadian organization thus appears critical for the maintenance of intestinal barrier integrity, especially in the context of injurious agents, such as alcohol. Circadian disruption may therefore represent a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease, as well as other conditions associated with intestinal hyperpermeability and an endotoxin-triggered inflammatory state.

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

“…Melatonin is a powerful antioxidant and is known in multiple animal models to be protective of colitis and intestinal hyperpermeability (26,30), including ethanol-induced intestinal hyperpermeability (42). Our finding is also supported by our animal data that alcohol-fed rodents that have circadian alteration induced either environmentally (light/dark phase shift) or by genetic manipulation (clock mutant) have increased alcohol-induced hyperpermeability and liver pathology (43).…”

“…Our recent work showed that alcohol in-creased circadian clock genes, CLOCK and PER2, in intestinal epithelial cells, CaCo-2 cells, and blocking CLOCK or PER2 with small-interfering RNA prevented alcohol-induced hyperpermeability (44). Our subsequent studies in mice have shown that circadian disruption, either environmental or genetic, increases alcohol-induced intestinal permeability and liver injury (43). Therefore in both in vitro and in vivo models, circadian homeostasis appears critical to intestinal barrier function in response to an injurious agent like alcohol.…”

Micro‐RNA‐155 Deficiency Prevents Alcohol‐Induced Serum Endotoxin Increase and Small Bowel Inflammation in Mice

“…However, the increase in serum-endotoxin level was transient after acute alcohol binge and returned to normal by 12 hours after alcohol intake. LBP, an acute phase protein produced by the liver, is induced by and binds to endotoxin (Summa et al, 2013). Serum-LBP was induced 12 hours after acute alcohol gavage and was also increased after 5 weeks of chronic alcohol feeding compared to nonalcohol controls (Fig.…”

Leaky gut: mechanisms, measurement and clinical implications in humans

“…It is also important to note that intestinal permeability is influenced by several factors, which are not always considered in the publications, including the circadian cycle40 and stress 41…”