Chronic alcohol consumption compromises gut barrier integrity and promotes endotoxemia: Implications for sepsis susceptibility in immunocompromised hosts

Animal Models and Experimental Medicine · Published 2026-05-01 · DOI 10.1002/ame2.70218

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Abstract

Abstract Background Gut barrier integrity prevents microbial translocation and systemic infection. Chronic alcohol disrupts this barrier, but its role in infection susceptibility among immune‐compromised hosts remains unclear. We investigated how chronic alcohol promotes gut barrier dysfunction, endotoxemia, and dysbiosis, predisposing to bacterial translocation and sepsis. Methods Twenty‐four‐week‐old female FcγRIIb−/− and wild‐type mice received oral gavage of 35% ethanol (4.2 g/kg/day) or water for 10 weeks. Gut barrier integrity was assessed by serum endotoxin, FITC‐dextran permeability, ileal claudin‐1, and intestinal IgG/neutrophil infiltration. Systemic inflammation was evaluated by serum TNF‐α, IL‐1β, and IL‐6; gut microbiota by 16S rRNA sequencing. Bone marrow–derived macrophages and hepatocytes from both genotypes were stimulated with LPS or ethanol to assess inflammatory responses, mitochondrial damage, and cGAS‐STING activation. Results Chronic alcohol induced gut barrier dysfunction in both groups, with more severe effects in FcγRIIb−/− mice, which showed marked increases in serum endotoxin and FITC‐dextran permeability, reduced claudin‐1, and enhanced intestinal IgG deposition with neutrophil accumulation. Serum TNF‐α, IL‐1β, and IL‐6 were significantly elevated, reflecting a sepsis‐like profile. Alcohol induced dysbiosis with an increased Firmicutes‐to‐Bacteroidota ratio, elevated Lachnospiraceae, and reduced Alistipes, Bacteroides, and Odoribacter. In vitro, LPS elicited stronger inflammation than ethanol in both cell types, with FcγRIIb−/− cells producing greater cytokine levels. Both stimuli caused comparable mitochondrial damage and cGAS‐STING activation. Conclusions Alcohol‐induced gut barrier dysfunction, endotoxemia, and dysbiosis predispose to bacterial translocation and early sepsis, particularly in hosts with impaired inhibitory Fcγ receptor signaling, supporting gut barrier preservation as a strategy for preventing alcohol‐associated infections and sepsis.

Abstract from DOAJ. Public domain (CC0 1.0).

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Publication details

Year
2026

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