Duodenal macrophages depletion and dysfunction contribute to gut barrier dysfunction in alcohol use disorder

In alcohol use disorder (AUD), duodenal macrophage number are reduced, but the underlying mechanisms and consequences for gut permeability remain unknown. Actively drinking AUD patients undergoing standardized inpatient detoxification and healthy controls were enrolled. Fasting blood samples and duodenal biopsies were analyzed using proteomics, histology, multiplex immunohistofluorescence, flow cytometry, and quantitative polymerase chain reaction. Circulating monocytes were differentiated ex vivo into macrophages to assess migration, differentiation, phagocytosis, and cytokine release following stimulation with bacterial products. Gut permeability was evaluated using urinary 51Chromium- ethylenediaminetetraacetic acid excretion, and plasma surrogate markers of microbial translocation. AUD patients showed markedly reduced duodenal macrophages despite increased circulating monocytes and tissue monocyte-attracting chemokines. AUD monocytes exhibited reduced CCR2 expression and downregulation of tissue proteins involved in adhesion and trans-endothelial migration, thereby decreasing mucosal infiltration. Early macrophage differentiation associated was impaired, with reduced CSF1, CSF2, IL-34, and CSF1 receptor expression. Despite preserved phagocytic capacity, residual tissue macrophages displayed a mixed immune phenotype with reduced expression of scavenger receptors involved in microbial responses and cytokine hyporesponsiveness to lipopolysaccharide and peptidoglycan. Reduced macrophage numbers correlated with increased intestinal permeability and markers of microbial translocation. These results link disruption of the duodenal monocyte-macrophage axis to intestinal barrier failure in AUD.