Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia‐inducible factor, promotes intestinal integrity, prevents inflammation, and ameliorates alcohol‐induced liver injury

Abstract

Gut‐derived endotoxin is a critical factor in the development and progression of alcoholic liver disease (ALD). Probiotics have been used to treat animal models of alcohol‐induced liver injury associated with gut leakiness and endotoxemia as well as human ALD. However, the mechanism(s) of their beneficial action are not well defined. We hypothesized that alcohol impaired the adaptive response induced hypoxia‐inducible factor (HIF), and that probiotic supplementation could attenuate this impairment and restore the barrier function in a mouse model of ALD by increasing HIF responsive proteins such as intestinal trefoil factor; thus reversing established ALD. C57BJ/6N mice were fed the Lieber deCarli diet containing 5% alcohol for 8 weeks. Lactobacillus rhamnosus GG (LGG) were supplemented in the last two weeks. LGG supplementation significantly reduced alcohol‐induced endotoxemia, hepatic steatosis, TNF‐α level and improved liver function. LGG restored alcohol‐induced reduction in the protein levels of HIF‐2α and intestinal trefoil factor and normalized mRNA expression of toll‐like receptors in the liver. 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‐1α/2α abolished the LGG effects, indicating that the protective effect of LGG is HIF‐dependent. This 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.