Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Pathology and Inflammation
MedicalResearch.com: What are the main findings of the study?
Answer: The main findings of the study were that disruption of circadian rhythms, which we achieved using independent genetic and environmental strategies in mice, leads to impaired function of the intestinal epithelial barrier. This loss of epithelial barrier integrity, which has been associated with numerous diseases, results in “gut leakiness,” a phenomenon in which endotoxin from gut bacteria can cross the intestinal wall and enter circulation, promoting inflammation. In particular, using in a disease model of gut-derived endotoxemia and inflammation, alcoholic liver disease, we found the circadian disruption interacted with alcohol, leading to increased gut leakiness, inflammation and liver damage.
MedicalResearch.com: Were any of the findings unexpected?
Answer: One surprising finding was that chronically exposing mice to phase shifts of the light:dark cycle, in a model of shift work in humans, lead to increased gut leakiness that was similar in magnitude to that caused by alcohol, a known factor causing intestinal barrier damage. This suggests that disruption of circadian rhythms alone, without alcohol, may be sufficient to injure or contribute to the damage of the intestinal epithelial barrier, which would result in chronic, non-pathogen-mediated inflammation, a common characteristic of many diseases affecting the Western world and other areas adopting aspects of the Western lifestyle.
MedicalResearch.com: What should clinicians and patients take away from your report?
Answer: Circadian rhythms and sleep are important physiological processes and behaviors to consider when it comes to discussions of health and disease. Strategies designed to improve the organization of circadian rhythms and sleep-wake cycles, such as avoiding exposure to light at night, getting sufficient sleep and maintaining a regular schedule, may be beneficial in promoting and maintaining health. Specifically, with respect to our study, such approaches may limit the progression of alcohol-induced gut leakiness, inflammation and liver pathology.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Answer: Future studies aimed at fully characterizing the mechanisms underlying the connection between circadian rhythms and the regulation of the intestinal epithelial barrier would be a useful extension of this study. We found that altered cytoplasmic localization of the tight junction protein occludin, which helps forms the intestinal barrier by linking adjacent cells together, may contribute to the observed results. However, additional work will be helpful in determining other mechanisms, which may lead to new diagnostic or therapeutic strategies.
Summa KC, Voigt RM, Forsyth CB, Shaikh M, Cavanaugh K, et al. (2013) Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation. PLoS ONE 8(6): e67102. doi:10.1371/journal.pone.0067102