Ethanol, acetaldehyde, lipopolysaccharide, and neutrophil extracellular traps: four-pronged attack on gut epithelial barrier in alcohol use disorder.

The intestinal epithelial barrier is formed by epithelial cells and their associated junctional complexes, comprising tight junctions, adherens junctions, and desmosomes. The junctional complex is composed of specialized junctional proteins that regulate nutrient permeability across the gut epithelium, while preventing penetration of pathogenic bacteria and toxins. Disruption of the junctional complex integrity and tampering with the junctional protein function lead to intestinal hyperpermeability, a phenomenon known as "leaky gut." This leakiness results in endotoxemia and systemic inflammation, which together orchestrate metabolic diseases of multiple organs, notably fatty liver and hepatitis, obesity, diabetes, cardiovascular lesions, renal disease, and CNS disorders. This article reviews the molecular and signaling mechanisms by which ethanol and its metabolite acetaldehyde, and bacterial lipopolysaccharide downregulate and redistribute the junctional proteins, thereby compromising the gut epithelial barrier function resulting in hyperpermeability. These data are gathered from investigations with patients with alcohol use disorder, alcohol-fed animals, and intestinal cell culture models. The review also covers the emerging role of neutrophil-derived neutrophil extracellular traps in executing the pathophysiology of the intestinal epithelial barrier in conditions of intestinal inflammation associated with alcohol consumption, experimental intestinal injury, colitis, and inflammatory bowel diseases, enteric nutrition, and diabetes. Thus, adequate nutritional support is essential for sustaining gut health and maintaining the barrier function. When the gut barrier is compromised, the intestine becomes a "portal", leading to systemic metabolic disease pathogenesis.