Such_Saturation
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Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation
Here we report, for the first time, that circadian disorganization causes increased permeability of the intestinal epithelial barrier in mice. Both genetic and environmental strategies of circadian disruption result in gut leakiness and promote alcohol-induced intestinal hyperpermeability, endotoxemia and liver steatosis. Phase-shifting of the light:dark cycle also increases hepatic cell injury in response to chronic alcohol consumption. These results indicate that circadian organization has a critical function in the maintenance of intestinal barrier integrity and suggest that circadian disruption may be a previously unrecognized risk factor for alcohol-induced liver injury.
The circadian clock imposes temporal organization to ongoing physiological and biochemical processes at multiple levels, thus optimizing function and, presumably, enhancing fitness. Therefore, circadian disruption is expected to result in adverse physiological consequences detrimental to the health and well-being of the organism. Indeed, a rapidly accumulating body of evidence supports this hypothesis. In humans, shift workers are known to be at increased risk for a number of chronic diseases and cardiometabolic abnormalities. In rodents, animals harboring mutations of core circadian clock genes exhibit multiple physiological and behavioral abnormalities. Chronic circadian disruption, achieved with repeated exposure to phase shifts of the light:dark cycle, accelerates and/or exacerbates numerous pathologies in rodents, and increases mortality in hamsters with a genetic predisposition to cardiomyopathy and in aged mice. These studies, as well as others, support a model in which the adverse effects of circadian disruption become evident in the presence of a physiological “challenge,” such as a genetic predisposition to disease, aging, a high-fat diet, pregnancy or chemically-induced colitis. Thus, it may be appropriate to consider circadian disruption as a “second hit” that can promote disease in susceptible individuals.
Interestingly, most, if not all, pathologies associated with disrupted circadian organization share non-pathogen mediated inflammation as a common characteristic. For example, there is substantial evidence from studies in humans and in rodent models, linking circadian disruption and metabolic syndrome, a constellation of abnormalities characterized, at least in part, by inflammation. Recently, it was shown that exposure to chronic phase shifts of the light:dark cycle in mice caused significant alteration and dysregulation of immune and inflammatory responses, particularly involving peritoneal macrophages that respond to endotoxin, however the mechanism(s) of circadian disruption-induced inflammation is not well-established.
Here we report, for the first time, that circadian disorganization causes increased permeability of the intestinal epithelial barrier in mice. Both genetic and environmental strategies of circadian disruption result in gut leakiness and promote alcohol-induced intestinal hyperpermeability, endotoxemia and liver steatosis. Phase-shifting of the light:dark cycle also increases hepatic cell injury in response to chronic alcohol consumption. These results indicate that circadian organization has a critical function in the maintenance of intestinal barrier integrity and suggest that circadian disruption may be a previously unrecognized risk factor for alcohol-induced liver injury.
The circadian clock imposes temporal organization to ongoing physiological and biochemical processes at multiple levels, thus optimizing function and, presumably, enhancing fitness. Therefore, circadian disruption is expected to result in adverse physiological consequences detrimental to the health and well-being of the organism. Indeed, a rapidly accumulating body of evidence supports this hypothesis. In humans, shift workers are known to be at increased risk for a number of chronic diseases and cardiometabolic abnormalities. In rodents, animals harboring mutations of core circadian clock genes exhibit multiple physiological and behavioral abnormalities. Chronic circadian disruption, achieved with repeated exposure to phase shifts of the light:dark cycle, accelerates and/or exacerbates numerous pathologies in rodents, and increases mortality in hamsters with a genetic predisposition to cardiomyopathy and in aged mice. These studies, as well as others, support a model in which the adverse effects of circadian disruption become evident in the presence of a physiological “challenge,” such as a genetic predisposition to disease, aging, a high-fat diet, pregnancy or chemically-induced colitis. Thus, it may be appropriate to consider circadian disruption as a “second hit” that can promote disease in susceptible individuals.
Interestingly, most, if not all, pathologies associated with disrupted circadian organization share non-pathogen mediated inflammation as a common characteristic. For example, there is substantial evidence from studies in humans and in rodent models, linking circadian disruption and metabolic syndrome, a constellation of abnormalities characterized, at least in part, by inflammation. Recently, it was shown that exposure to chronic phase shifts of the light:dark cycle in mice caused significant alteration and dysregulation of immune and inflammatory responses, particularly involving peritoneal macrophages that respond to endotoxin, however the mechanism(s) of circadian disruption-induced inflammation is not well-established.
