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Chronic Alcohol Ingestion Worsens Survival and Alters Gut Epithelial Apoptosis and CD8+ T Cell Function After Pseudomonas Aeruginosa Pneumonia-Induced Sepsis

Klingensmith, Nathan J.*; Fay, Katherine T.*; Lyons, John D.*; Chen, Ching-wen*; Otani, Shunsuke*,†; Liang, Zhe*; Chihade, Deena B.*; Burd, Eileen M.; Ford, Mandy L.§; Coopersmith, Craig M.*

doi: 10.1097/SHK.0000000000001163
Basic Science Aspects

ABSTRACT Mortality is higher in septic patients with a history of alcohol use disorder than in septic patients without a history of chronic alcohol usage. We have previously described a model of chronic alcohol ingestion followed by sepsis from cecal ligation and puncture in which alcohol-fed septic mice have higher mortality than water-fed septic mice, associated with altered gut integrity and increased production of TNF and IFNγ by splenic CD4+ T cells without alterations in CD8+ T cell function. The purpose of this study was to determine whether this represents a common host response to the combination of alcohol and sepsis by creating a new model in which mice with chronic alcohol ingestion were subjected to a different model of sepsis. C57Bl/6 mice were randomized to receive either alcohol or water for 12 weeks and then subjected to Pseudomonas aeruginosa pneumonia. Mice were sacrificed either 24 hours after the onset of sepsis or followed for survival. Alcohol-fed septic mice had significantly higher 7-day mortality than water-fed septic mice (96% vs 58%). This was associated with a 5-fold increase in intestinal apoptosis in alcohol-fed septic animals, accompanied by an increase in the pro-apoptotic protein Bax. Serum IL-6 levels were higher and IL-2 levels were lower in alcohol-fed septic mice. In contrast, CD8+ T cell frequency was lower in alcohol-fed mice than water-fed septic mice, associated with increased production of IFNγ and TNF in stimulated splenocytes. No significant differences were noted in CD4+ T cells, lung injury or bacteremia. Mice with chronic alcohol ingestion thus have increased mortality regardless of their septic insult, associated with changes in both the gut and the immune system.

*Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA

Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA

§Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, GA

Address reprint requests to Craig M. Coopersmith, MD, 101 Woodruff Circle, Suite WMB 5105, Atlanta, GA 30322. E-mail:

Received 9 January, 2018

Revised 29 January, 2018

Accepted 10 April, 2018

MLF and CMC: This work reflects equal contributions from these authors’ laboratories.

This work was supported by funding from the National Institutes of Health (GM072808, GM095442, GM104323, GM109779, GM113228, GM117895).

The authors report no conflicts of interest.

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