Functional and Transcriptional Effects of a Hydrogen Sulfide Donor on the Intestinal Epithelial Barrier

Abstract The intestinal epithelial barrier is essential for protecting against pathogens and toxins while permitting nutrient and water absorption. Barrier dysfunction is a hallmark of inflammatory diseases affecting the gastrointestinal (GI) tract and beyond. Hydrogen sulfide (H₂S) has emerged as a critical regulator of intestinal homeostasis. This study examines the effects of the H₂S-releasing compound 4-hydroxithiobenzamide (TBZ) on epithelial barrier integrity. While TBZ did not prevent interferon-γ and tumor necrosis factor-α (IFN/TNF)-induced epithelial cell death, it reversed cytokine-induced increases in transepithelial permeability. Interestingly, TBZ alone elevated paracellular permeability, yet normalized it under inflammatory conditions, indicating a context-dependent effect. H₂S-producing enzymes localized apically in intestinal epithelial cells, suggesting spatial regulation. Transcriptomic analysis implicated oxidative phosphorylation as a pathway mediating TBZ’s effects. These findings advance our understanding of H₂S in intestinal barrier regulation and support TBZ as a candidate therapeutic agent for conditions marked by barrier dysfunction in an inflammatory context.