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

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.

Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease

“…Early studies determined that exposure of ethanol to the human colonic Caco-2 cell line triggered apoptosis in these epithelial cells [ 128 ]. Although a mouse model of chronic ethanol exposure alone displayed no significant changes in apoptotic protein markers or intestinal permeability in the jejunum [ 129 ], binge alcohol exposure elevated endotoxin levels in rodent models, pointing to the development of a leaky gut in these animals [ 130 , 131 ]. The effects of binge alcohol exposure on time- and dose-dependent gut permeability change, elevated endotoxemia, and fatty liver injury were confirmed by other laboratories [ 121 , 132 , 133 ].…”

Pathophysiology and protective approaches of gut injury in critical illness

“…This induces an increase of apoptosis and decrease of proliferation of small bowel mucosal cells, leading to the thinning of gut mucosa [ 29 ]. The resulting gut damage is exacerbated in the presence of chronic comorbidities such as cancer and chronic alcohol abuse [ 30 , 31 ]. Such injuries result in the impairment of the gut barrier and dysregulation of intestinal microbiota [ 32 , 33 ].…”

Silencing of lncRNA MIAT alleviates LPS-induced pneumonia via regulating miR-147a/NKAP/NF-κB axis

“…Pneumonia is often accompanied by lung injury [ 12 , 13 ], which turns into pulmonary edema and neutrophil accumulation [ 14 , 15 ]. Zhang et al [ 16 ] found that lncRNA FOXD3-AS1 was the most significantly upregulated lncRNAs in hyperoxia-induced acute lung injury model.…”