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.
Highlights
Mammalian circadian organization consists of a cell-autonomous molecular pacemaker active in most cells of the body that drives the expression of thousands of genes (i.e., ‘‘clockcontrolled genes’’) and regulates numerous biochemical and physiological rhythms [1]
Circadian Disruption – Genetic model Using ClockD19/D19 mutant mice as a genetic model of circadian disorganization [23,24], we observed that animals homozygous for the ClockD19 mutation exhibited significantly increased intestinal permeability, as measured by the urinary excretion of orally administered non-metabolized, non-absorbed sugars (Figure 2; p,0.001, Student’s t-test)
Utilizing chronic alcohol consumption as a model to induce intestinal hyperpermeability [14], we sought to determine whether genetic perturbation of the circadian system by the ClockD19
Summary
Mammalian circadian organization consists of a cell-autonomous molecular pacemaker active in most cells of the body that drives the expression of thousands of genes (i.e., ‘‘clockcontrolled genes’’) and regulates numerous biochemical and physiological rhythms [1]. We recently demonstrated that chronic circadian disruption worsened dextran sodium sulfate (DSS)-induced colitis in mice: repeated phase shifts of the light:dark (LD) cycle accelerated disease onset, worsened severity of histopathological damage, exacerbated inflammation and increased mortality [9]. This finding provided compelling evidence that perturbation of the circadian clock renders intestinal epithelial cells vulnerable to injury. Sleep deprivation, both acute and chronic, augments inflammation and pathology in DSS-treated mice [10]. These observations indicate that circadian organization is important for optimal gastrointestinal physiological function and highlight the relevance of disruption of circadian rhythms for pathologies within the gastrointestinal tract, in particular those involving intestinal epithelial barrier integrity
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