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June 27, 2013

Circadian Clock Disruption May be a Factor in Developing Liver Disease
 

(Chicago)—A research team from Rush University Medical Center and Northwestern University has discovered that circadian rhythm disruption may be a factor in developing cirrhosis, also known as alcoholic liver disease, when combined with heavy alcohol consumption. The study results were published in June by the journal PLOS ONE.

In working with and studying patients with alcoholic liver disease, Dr. Ali Keshavarzian, a gastroenterologist at Rush University Medical Center and senior author of the paper, suspected circadian rhythms could be a contributing factor to the disease. He observed that some patients with inflammatory bowel disease (inflammation in the intestine and/or colon) had flare-ups of symptoms when working nights, but they could control the disease when working the day shift.

“Non-pathogen chronic inflammation is the major cause of many chronic diseases that are common in western societies and developing countries who have adopted western lifestyle. Examples of these diseases are Crohn’s and ulcerative colitis, Parkinson disease, diabetes, multiple sclerosis, autoimmune disease, cardiovascular disease just to name a few,” Keshavarzian said.

Steatohepatitis, a condition characterized by swelling of the abdomen weight gain and loss of appetite that can lead to the development of cirrhosis, develops in about 30 percent of alcoholics. The research team examined why a subset of heavy drinkers are at risk.

In alcoholic steatohepatitis, toxins are released into the bloodstream by escaping the epithelial cell lining of the intestines, made possible by increased permeability of the intestines, or leaky gut.

“Recent studies have shown that intestinal bacteria is the primary trigger for this inflammation and gut leakiness is one of the major causes. However, the trigger for gut leakiness is not known. Our study suggest that disruption of circadian and sleep rhythms that are part of life in the industrial societies could be the susceptibility and trigger for it,” he said. Keshavarzian is the senior author of the paper and the director of the Division of Digestive Diseases and the Josephine M. Dyrenforth Chair of Gastroenterology.

Circadian clock controls daily patterns of physiological and behavioral patterns relative to the light and dark cycle by generating and organizing genetic signaling and biochemical rhythms in cells and tissues throughout the body. Circadian clock genes have been shown to regulate several organs in the body, including the gastrointestinal tract.

Dr. Fred W. Turerk, the Charles E. and Emma H. Morrison Professor of Biology at Northwestern’s Weinberg College of Arts and Sciences and a co-author of the paper, helped investigate the relationship between circadian rhythms and the disease.

The team studied mice that had internal clocks that were uncoordinated with the natural light-dark cycle. A separate group of mice had circadian disruption due to a faulty gene. Both groups of mice were given alcohol, where the team found that the combination of alcohol and circadian disruption is a destructive combination that can lead to alcoholic liver disease.

Keshavarzian and Turek groups studies the effect of disruption of circadian rhythm in one animal model of colitis and noted that disruption of sleep and circadian rhythms that model shift work and chronic jet lag caused more severe colitis in mice. Keshavarzian has been studying the effect of gut leakiness to bacterial products in GI diseases for two decades and since the mice model of colitis is associated with leaky gut, he proposed that disruption of circadian rhythms from shift work could make intestine more susceptible to leakiness and thus proposed to test its effect in model of alcoholic liver disease where subset of alcoholics develop gut leakiness and liver disease in order to find out whether shift work is the susceptibility factor to promote liver injury.  

The paper, titled “Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Pathology and Inflammation,” is available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067102.

In addition to Turek, Summa and Keshavarzian, other authors of the paper are Robin M. Voigt of Rush University Medical Center who is the co-first author of the paper, Martha Hotz Vitaterna and Kate Cavanaugh, of Northwestern;, Christopher B. Forsyth, Maliha Shaikh and Yueming Tang, of Rush University Medical Center; and Shiwen Song, of the American Society for Clinical Pathology.

 


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