Lactobacillus rhamnosus GG Treatment Potentiates Intestinal Hypoxia-Inducible Factor, Promotes Intestinal Integrity 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 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 ALD by increasing HIF-responsive proteins (eg, intestinal trefoil factor) and reversing established ALD. 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-2α 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-1α/2α 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.

Intestinal fungi contribute to development of alcoholic liver disease

“…We have previously demonstrated that dysbiosis-induced intestinal inflammation increases intestinal permeability (23,35). Reducing bacteria with nonabsorbable antibiotics and restoration of bacterial eubiosis abolishes the onset of an intestinal barrier dysfunction (23,36). Interestingly, decreasing intestinal fungal overgrowth with nonabsorbable antifungals did not alter gut barrier function, and intestinal permeability remained increased.…”

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…Chronic ethanol feeding causes a decline in the abundance of Bacteriodetes and Firmicutes phyla, with a proportional increase in the Gram-negative Proteobacteria. Oral administration of Lactobacillus rhamnosus GG attenuates the established alcohol-induced hepatic steatosis and liver injury in mouse models of ALD [208] . Probiotics create an anti-inflammatory milieu, decrease production of proinflammatory bacterial products, and improve barrier integrity leading to a decrease of endotoxin release.…”

“…In alcohol-treated mice, the PPARγ agonists, rosiglitazone and pioglitazone, increase circulating levels of adiponectin and expression of its receptors in the liver that is associated with SIRT1-AMPK signaling activation. This pathway correlates with the enhanced expression of fatty acid oxidation enzymes and reduction of alcohol-induced steatosis [207][208][209][210][211][212][213] . In addition, PPARγ agonists have anti-inflammatory effects that reduce cytokine expression such as TNF-α, IL-6 and MCP-1 in alcohol-fed mice [207] .…”

Review of randomized controlled trials of nutritional supplementation in people living with HIV

“…116 Modulation of gut microflora has been suggested as a safe and promising treatment in HIV infection. [117][118][119] Probiotics have been shown to have favorable effects on alcoholic liver disease in clinical and experimental animal research. [50][51][52]119 L. rhamnosus Gorbach-Goldin is one of the most widely studied probiotic strains with many well-documented benefits on several GI conditions and diseases.…”

“…[117][118][119] Probiotics have been shown to have favorable effects on alcoholic liver disease in clinical and experimental animal research. [50][51][52]119 L. rhamnosus Gorbach-Goldin is one of the most widely studied probiotic strains with many well-documented benefits on several GI conditions and diseases. 105,120 A limited number of studies using probiotic supplementation have been conducted in HIV infection; [103][104][105][121][122][123] they have shown that probiotics were safe and effective in reducing diarrhea, nausea, and stabilizing CD4+ T-cell numbers.…”