Citation

Forsyth CB, Voigt RM, Burgess HJ, Swanson GR, Keshavarzian A. Alcohol 2014; 49(4): 389-398.

Affiliation

Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA; Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Department of Molecular Biophysics & Physiology, Rush University Medical Center, Chicago, IL, USA; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.

Copyright

(Copyright © 2014, Elsevier Publishing)

DOI

10.1016/j.alcohol.2014.07.021

PMID

25499101

Abstract

The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20-30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyperpermeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1-mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in Clock(▵19) mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our data support circadian mechanisms for alcohol-induced gut leakiness that could provide new therapeutic targets for ALD.

Language: en