title: 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.
authors.affiliation: College of Food Science and Engineering, Jilin Agricultural University, Changchun, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Irina
authors.initials: I
authors.lastname: Kirpich
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Ma
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004847:Epithelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007082:Ileum / Q000378:metabolism; D052201:Lacticaseibacillus rhamnosus; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse
references.citation: Alcohol Clin Exp Res. 2009 Oct;33(10):1836-46
references.pmid: 19645728
references.citation: Inflamm Bowel Dis. 2002 Mar;8(2):71-80
references.pmid: 11854603
references.citation: Mol Pharmacol. 2009 Jan;75(1):174-82
references.pmid: 18842833
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G625-33
references.pmid: 20167873
references.citation: Lab Invest. 2008 May;88(5):541-52
references.pmid: 18347582
references.citation: J Clin Invest. 2004 Oct;114(8):1098-106
references.pmid: 15489957
references.citation: Methods Mol Biol. 2008;447:171-83
references.pmid: 18369919
references.citation: Hepatol Res. 2005 Apr;31(4):187-92
references.pmid: 16890166
references.citation: J Hepatol. 2000 May;32(5):742-7
references.pmid: 10845660
references.citation: Biochim Biophys Acta. 2008 Mar;1778(3):660-9
references.pmid: 17854762
references.citation: Clin Exp Allergy. 2007 Apr;37(4):498-505
references.pmid: 17430345
references.citation: Proc Soc Exp Biol Med. 1994 Mar;205(3):243-7
references.pmid: 8171045
references.citation: Curr Opin Gastroenterol. 2006 Mar;22(2):85-9
references.pmid: 16462161
references.citation: J Pharmacol Exp Ther. 2001 Nov;299(2):442-8
references.pmid: 11602653
references.citation: J Hepatol. 2009 Mar;50(3):538-47
references.pmid: 19155080
references.citation: Gastroenterology. 1993 Dec;105(6):1643-50
references.pmid: 8253341
references.citation: Am J Physiol. 1999 Apr;276(4):G965-74
references.pmid: 10198341
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Sep;287(3):G497-502
references.pmid: 15331349
references.citation: Gastroenterology. 2004 Nov;127(5):1474-87
references.pmid: 15521016
references.citation: Gut. 2007 Nov;56(11):1495-7
references.pmid: 17938427
references.citation: World J Gastroenterol. 2006 Oct 7;12(37):5941-50
references.pmid: 17009391
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
references.pmid: 7539918
references.citation: Gastroenterology. 1999 May;116(5):1107-14
references.pmid: 10220502
references.citation: J Mol Med (Berl). 2007 Dec;85(12):1295-300
references.pmid: 18026919
references.citation: Toxicol Lett. 2009 Jul 10;188(1):70-6
references.pmid: 19433272
references.citation: Gut. 2006 Nov;55(11):1553-60
references.pmid: 16638791
references.citation: Mol Cell. 2008 May 23;30(4):393-402
references.pmid: 18498744
references.citation: Biochem Pharmacol. 2002 Sep;64(5-6):993-8
references.pmid: 12213597
references.citation: Sci STKE. 2007 Oct 09;2007(407):cm8
references.pmid: 17925579
references.citation: APMIS. 2011 Jan;119(1):49-56
references.pmid: 21143526
references.citation: J Clin Invest. 2002 Oct;110(7):993-1002
references.pmid: 12370277
references.citation: Cancer Res. 2002 Jun 15;62(12):3387-94
references.pmid: 12067980
references.citation: Gastroenterology. 2007 Feb;132(2):562-75
references.pmid: 17258729
references.citation: Therap Adv Gastroenterol. 2011 Jan;4(1):63-81
references.pmid: 21317995
references.citation: Gastroenterology. 1995 Jan;108(1):218-24
references.pmid: 7806045
references.citation: J Appl Toxicol. 1998 Jan-Feb;18(1):3-13
references.pmid: 9526828
references.citation: Nat Rev Gastroenterol Hepatol. 2010 May;7(5):281-7
references.pmid: 20368740
references.citation: J Exp Med. 2001 May 7;193(9):1027-34
references.pmid: 11342587
references.citation: Cell Mol Life Sci. 2009 Apr;66(8):1350-69
references.pmid: 19099184
references.citation: Alcohol. 2008 Dec;42(8):675-82
references.pmid: 19038698
references.citation: J Exp Med. 2003 Sep 1;198(5):783-96
references.pmid: 12939345
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Sep;299(3):G643-51
references.pmid: 20576917
references.citation: Hepatology. 2011 Jan;53(1):96-105
references.pmid: 21254165
references.citation: J Hepatol. 2008 Nov;49(5):821-30
references.pmid: 18674841
references.citation: J Hepatol. 2004 Feb;40(2):219-27
references.pmid: 14739091
references.citation: Alcohol. 2009 Mar;43(2):163-72
references.pmid: 19251117
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Apr;294(4):G1060-9
references.pmid: 18292183
references.citation: Nat Rev Immunol. 2009 Nov;9(11):799-809
references.pmid: 19855405
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Jun;298(6):G807-19
references.pmid: 20299599
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Pancreas. 2007 May;34(4):410-6
references.pmid: 17446839
references.citation: Biol Chem. 2010 Nov;391(11):1249-64
references.pmid: 20868231
references.citation: J Nutr. 2007 Aug;137(8):1901-7
references.pmid: 17634262
references.citation: J Dairy Sci. 2009 Jun;92(6):2400-8
references.pmid: 19447972
references.citation: Chin J Dig Dis. 2005;6(4):193-7
references.pmid: 16246229