Lactobacillus Rhamnosus GG Treatment Potentiates Intestinal Hypoxia-Inducible Factor, Promotes Intestinal Integrity and Ameliorates Alcohol-Induced Liver Injury

Am J Pathol. 2011 Dec;179(6):2866-75. doi: 10.1016/j.ajpath.2011.08.039.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Caco-2 Cells
  • Cell Membrane Permeability
  • Epithelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Ileum / metabolism
  • Lactobacillus rhamnosus*
  • Liver Diseases, Alcoholic / metabolism
  • Liver Diseases, Alcoholic / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • endothelial PAS domain-containing protein 1