期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 179, 期 6, 页码 2866-2875出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2011.08.039
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资金
- NIH [P01-AA017103, R01-AA015970, R01-DK071765, R37-AA010762, R01-AA018016, R01-AA018869, P30-AA019360, RC2-AA019385]
- Veterans Administration
- American Diabetes Association [07-07-JF-23]
- China Scholarship Council
- Jilin Provincial Government [20090576]
- Wenzhou Medical College
- Guanghua Foundation at Xi'an Jiaotong University
Gut-derived endotoxin is a critical factor in the development and progression of alcoholic liver disease (ALD). Probiotics can treat alcohol-induced liver injury associated with gut leakiness and endotoxemia in animal models, as well as in human ALD; however, the mechanism or mechanisms of their beneficial action are not well defined. We hypothesized that alcohol impairs the adaptive response-induced hypoxia-inducible factor (HIF) and that probiotic supplementation could attenuate this impairment, restoring barrier function in a mouse model of AID by increasing HIF-responsive proteins (eg, intestinal trefoil factor) and reversing established AID. C57BJ/6N mice were fed the Lieber DeCarli diet containing 5% alcohol for 8 weeks. Animals received Lactobacillus rhamnosus GG (LGG) supplementation in the last 2 weeks. LGG supplementation significantly reduced alcohol-induced endotoxemia and hepatic steatosis and improved liver function. LGG restored alcohol-induced reduction of HIF-2 alpha and intestinal trefoil factor levels. In vitro studies using the Caco-2 cell culture model showed that the addition of LGG supernatant prevented alcohol-induced epithelial monolayer barrier dysfunction. Furthermore, gene silencing of HIF-1 alpha/2 alpha abolished the LGG effects, indicating that the protective effect of LGG is HIF-dependent. The present study provides a mechanistic insight for utilization of probiotics for the treatment of ALD, and suggests a critical role for intestinal hypoxia and decreased trefoil factor in the development of ALD. (Am J Pathol 2011, 179:2866-2875; DOI.10.1016/j.ajpath.2011.08.039)
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