Amino acid transporter impairment driven by oxidative stress contributes to IEC dysfunction in alcohol-associated bowel disease.

Abstract

Alcohol-associated bowel disease (ABD), a classic consequence of alcohol abuse, is a significant underlying pathology closely linked to alcohol-related diseases and injuries. The dysfunction of intestinal epithelial cells (IECs) is a primary driver and fundamental pathological basis in ABD; however, the potential mechanisms have not yet been fully elucidated. In this study, ABD model was established by feeding C57BL/6N mice with Lieber- DeCarli alcohol diet. Transcriptomics of IECs isolated from ileum was performed to systematically delineate the profiles of genes expression differences in ABD. Gene editing was used to verify the mechanisms underlying alcohol-induced IECs damage. Antioxidant (MitoQ) was administrated to ABD mice to elucidate the concept that oxidative stress was involved in alcohol-stimulated IECs dysfunction. Our results showed that alcohol-fed significantly induced ileal structure and barrier impairment, tight junction proteins loss, intestinal permeability enhancement, and proinflammatory factors expression increase. Transcriptomics analysis revealed that amino acid (AA) transporters and redox-related pathways were the top down- and up-regulated pathways, respectively. Further verification confirmed that alcohol feeding inhibited the uptake capacity of fluorescently labeled-AA by IECs. While decreased AA transporters were positively associated with ileal injury indices. Genetically knocking-down AA transporters, including Slc15a1, Slc6a19, and Slc3a1, aggravated ethanol exposure stimulated tight junction proteins transcriptional repression or cell damage in cultured IECs. While MitoQ intervention reversed alcohol-suppressed expression and activity of AA transporters and further IECs damage. In summary, AA transporters impairment contributes to chronic-plus-binge alcohol intake-induced IECs dysfunction in ABD. Antioxidant treatment might be a promising choice for ABD management.