title: Chronic alcohol ingestion increases mortality and organ injury in a murine model of septic peritonitis.
abstract: BACKGROUND
  Patients admitted to the intensive care unit with alcohol use disorders have increased morbidity and mortality. The purpose of this study was to determine how chronic alcohol ingestion alters the host response to sepsis in mice.
  
  
  METHODS
  Mice were randomized to receive either alcohol or water for 12 weeks and then subjected to cecal ligation and puncture. Mice were sacrificed 24 hours post-operatively or followed seven days for survival.
  
  
  RESULTS
  Septic alcohol-fed mice had a significantly higher mortality than septic water-fed mice (74% vs. 41%, p = 0.01). This was associated with worsened gut integrity in alcohol-fed mice with elevated intestinal epithelial apoptosis, decreased crypt proliferation and shortened villus length. Further, alcohol-fed mice had higher intestinal permeability with decreased ZO-1 and occludin protein expression in the intestinal tight junction. The frequency of splenic and bone marrow CD4+ T cells was similar between groups; however, splenic CD4+ T cells in septic alcohol-fed mice had a marked increase in both TNF and IFN-γ production following ex vivo stimulation. Neither the frequency nor function of CD8+ T cells differed between alcohol-fed and water-fed septic mice. NK cells were decreased in both the spleen and bone marrow of alcohol-fed septic mice. Pulmonary myeloperoxidase levels and BAL levels of G-CSF and TFG-β were higher in alcohol-fed mice. Pancreatic metabolomics demonstrated increased acetate, adenosine, xanthine, acetoacetate, 3-hydroxybutyrate and betaine in alcohol-fed mice and decreased cytidine, uracil, fumarate, creatine phosphate, creatine, and choline. Serum and peritoneal cytokines were generally similar between alcohol-fed and water-fed mice, and there were no differences in bacteremia, lung wet to dry weight, or pulmonary, liver or splenic histology.
  
  
  CONCLUSIONS
  When subjected to the same septic insult, mice with chronic alcohol ingestion have increased mortality. Alterations in intestinal integrity, the host immune response, and pancreatic metabolomics may help explain this differential response.
authors.affiliation: Department of Surgery and Emory Center for Critical Care, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Benyam P
authors.initials: BP
authors.lastname: Yoseph
authors.forename: Elise
authors.initials: E
authors.lastname: Breed
authors.forename: Christian E
authors.initials: CE
authors.lastname: Overgaard
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Ward
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liang
authors.forename: Maylene E
authors.initials: ME
authors.lastname: Wagener
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lexcen
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Lusczek
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Beilman
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Burd
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.forename: David M
authors.initials: DM
authors.lastname: Guidot
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D000431:Ethanol / Q000009:adverse effects*; D007109:Immunity / Q000187:drug effects / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D062793:Occludin / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000401:mortality*; D010539:Permeability / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000401:mortality*; D019108:Tight Junctions / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; D062793:Occludin; C568986:Ocln protein, mouse; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D000431:Ethanol; D009195:Peroxidase