Alcohol Injury Damages Intestinal Stem Cells

作者：Lu Rong; Voigt Robin M; Zhang Yongguo; Kato Ikuko; Xia Yinglin; Forsyth Christopher B; Keshavarzian Ali^*; Sun Jun^*

来源：Alcoholism: Clinical and Experimental Research , 2017, 41(4): 727-734.

DOI：10.1111/acer.13351

• Alcohol Exposure
• beta-Catenin
• Bmi1
• Enteroid
• Intestinal Stem Cells
• Lgr5
• Organoid Culture

Background: Alcohol consumption is associated with intestinal injury including intestinal leakiness and the risk of developing progressive gastrointestinal cancer. Alcoholics have disruption of intestinal barrier dysfunction that persists weeks after stopping alcohol intake, and this occurs in spite of the fact that intestinal epithelial cells turn over every 3 to 5days. The renewal and functional regulation of the intestinal epithelium largely relies on intestinal stem cells (ISCs). Chronic inflammation and tissue damage in the intestine can injure stem cells including accumulation of mutations that may result in ISC dysfunction and transformation. ISCs are a key element in intestinal function and pathology; however, very little is known about the effects of alcohol on ISCs. We hypothesize that dysregulation of ISCs is one mechanism by which alcohol induces long-lasting intestinal damage.
Methods: In Vivo: Small intestinal samples from alcohol- and control-fed mice were assessed for ISC markers (Lgr5 and Bmi1) and the changes of the beta-catenin signaling using immunofluorescent microscopy, Western blotting, and RT-PCR. Ex Vivo: Organoids were generated from small intestine tissue and subsequently exposed to alcohol and analyzed for ISC markers, beta-catenin signaling.
Results: Chronic alcohol consumption significantly decreased the expression of stem cell markers, Bmi1 in the small intestine of the alcohol-fed mice and also resulted in dysregulation of the beta-catenin signalingan essential regulator of its target gene Lgr5 and ISC function. Exposure of small intestine-derived organoids to 0.2% alcohol significantly reduced the growth of the organoids, including budding, and total surface area of the organoid cultures. Alcohol also significantly decreased the expression of Lgr5, p-beta-catenin (ser552), and Bmi1 in the organoid model.
Conclusions: Both chronic alcohol feeding and acute exposure of alcohol resulted in ISC dysregulation which might be one mechanism for alcohol-induced long-lasting intestinal damage.

• 出版日期2017-4