Unraveling the gastrointestinal tract's response to alcohol binges: Neutrophil recruitment, neutrophil extracellular traps, and intestinal injury.

BACKGROUND

Excessive alcohol consumption results in gastrointestinal (GI) tract dysfunction, including disruption of the intestinal barrier and exposure of the liver to microbes and gut-derived pathogen-associated molecular patterns (PAMPs). The upper GI tract is exposed to the highest amount of alcohol, but little is known about alcohol's impact on GI inflammation. This study aimed to evaluate the initial effects of alcohol binges on GI inflammation.

METHODS

A murine model of binge drinking was established with daily oral gavages of alcohol (3.5 g/kg) for 3 days in C57BL/6J female mice. The proximal small intestine (PSI), distal small intestine (DSI), and colon were evaluated for inflammation at 3 and 24 h after the last binge. To determine whether reactive oxygen species (ROS) contribute to intestinal inflammation, a subset of mice were given 500 mg/kg N-acetyl-cysteine (NAC) with alcohol via gavage. To assess the role of neutrophil extracellular traps (NETs), mice were treated 1 h before the alcohol binges with 5 mg/kg of DNase, a nonspecific inhibitor of NETs.

RESULTS

Alcohol binges induced a PSI enteropathy with neutrophil recruitment, activation, NETs, and increased serum endotoxin without significant changes in PSI pro-inflammatory cytokines. Neutrophil recruitment and serum endotoxin normalized 24 h after the last binge with persistent PSI villous blunting. While alcohol generated ROS, administration of the antioxidant, NAC, failed to prevent the PSI enteropathy, neutrophil activation, or increased serum endotoxin. DNase treatment improved the PSI enteropathy and reduced serum endotoxin, neutrophil recruitment, and neutrophil activation. We found robust upregulation of Gal-3 and CXCL10 in the PSI after alcohol binges is associated with neutrophil recruitment and activation.

CONCLUSION

Alcohol binges result in a PSI enteropathy, transient infiltration of neutrophils, and NETs that are independent of ROS production. Treatment with DNase, a nonspecific inhibitor of NETs, mitigates alcohol-induced PSI enteropathy, neutrophil recruitment and bacterial translocation.