title: Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury.
abstract: The therapeutic effects of probiotic treatment in alcoholic liver disease (ALD) have been studied in both patients and experimental animal models. Although the precise mechanisms of the pathogenesis of ALD are not fully understood, gut-derived endotoxin has been postulated to play a crucial role in hepatic inflammation. Previous studies have demonstrated that probiotic therapy reduces circulating endotoxin derived from intestinal gram-negative bacteria in ALD. In this study, we investigated the effects of probiotics on hepatic tumor necrosis factor-α (TNFα) production and inflammation in response to chronic alcohol ingestion. Mice were fed Lieber DeCarli liquid diet containing 5% alcohol for 8weeks, and Lactobacillus rhamnosus GG (LGG) was supplemented in the last 2 weeks. Eight-week alcohol feeding caused a significant increase in hepatic inflammation as shown by histological assessment and hepatic tissue myeloperoxidase activity assay. Two weeks of LGG supplementation reduced hepatic inflammation and liver injury and markedly reduced TNFα expression. Alcohol feeding increased hepatic mRNA expression of Toll-like receptors (TLRs) and CYP2E1 and decreased nuclear factor erythroid 2-related factor 2 expression. LGG supplementation attenuated these changes. Using human peripheral blood monocytes-derived macrophages, we also demonstrated that incubation with ethanol primes both lipopolysaccharide- and flagellin-induced TNFα production, and LGG culture supernatant reduced this induction in a dose-dependent manner. In addition, LGG treatment also significantly decreased alcohol-induced phosphorylation of p38 MAP kinase. In conclusion, probiotic LGG treatment reduced alcohol-induced hepatic inflammation by attenuation of TNFα production via inhibition of TLR4- and TLR5-mediated endotoxin activation.
authors.affiliation: Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Irina
authors.initials: I
authors.lastname: Kirpich
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Ma
authors.forename: Cuiling
authors.initials: C
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.forename: Craig
authors.initials: C
authors.lastname: McClain
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004731:Endotoxins / Q000009:adverse effects / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism; D005408:Flagellin / Q000009:adverse effects / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000628:therapy*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D052201:Lacticaseibacillus rhamnosus; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000628:therapy*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D019936:Probiotics / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D014409:Tumor Necrosis Factor-alpha; D005408:Flagellin; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Alcohol; Inflammation; Liver; Probiotics; TNF