title: Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury.
abstract: OBJECTIVE
  Impaired gut-liver axis is a potential factor contributing to alcoholic liver disease. Ethanol depletes intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is altered negatively following chronic ethanol exposure. This study aimed to determine whether prophylactic tributyrin could protect the intestinal barrier and liver in mice during combined chronic-binge ethanol exposure.
  
  
  METHODS
  C57BL/6J mice exposed to 5% v/v ethanol-containing diet for 10 days received a single ethanol gavage (5 g/kg) 9 h before euthanasia. Control mice were isocalorically pair-fed maltose dextrin for ethanol. Diets were supplemented (5 mM) with tributyrin or glycerol. Intestine and liver disease activity was assessed histologically. Protein and mRNA expression of tight junction (TJ) proteins, toll-like receptors, and tumor necrosis factor-alpha were assessed. Caco-2 monolayers with or without ethanol exposure and/or sodium butyrate were used to test butyrate's direct effects on intestinal integrity.
  
  
  RESULTS
  Chronic-binge ethanol feeding impaired intestinal TJ protein co-localization staining; however, tributyrin co-treatment mitigated these effects. Ethanol depleted TJ and transepithelial electrical resistance in Caco-2 monolayers, but butyrate co-treatment reduced these effects. Hepatic toll-like receptor mRNA expression and tumor necrosis factor-alpha protein expression was induced by ethanol; however, the response was significantly dampened in mice co-treated with tributyrin. Tributyrin altered localization of both neutrophils and single hepatocyte death: Leukocytes and apoptotic hepatocytes localized predominantly around the portal tract in ethanol-only treated mice, whereas localization predominated around the central vein in ethanol-tributyrin mice.
  
  
  CONCLUSIONS
  Prophylactic tributyrin supplementation mitigated effects of combined chronic-binge ethanol exposure on disruption of intestinal TJ localization and intestinal permeability and liver injury.
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.|Pediatric Research Center, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Cresci
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Glueck
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Daniella
authors.initials: D
authors.lastname: Allende
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000188:drug therapy* / Q000517:prevention & control*; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D062725:Tight Junction Proteins / Q000378:metabolism; D014280:Triglycerides / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D062725:Tight Junction Proteins; D014280:Triglycerides; D000431:Ethanol; C005830:tributyrin
keywords: alcoholic liver disease; chronic-binge ethanol; gut permeability; tight junction proteins; tributyrin