Tricobalt tetraselenide nanoparticles improve intestinal barrier function by reshaping the gut microbiota and fortifying epithelial tight junctions

The disrupted intestinal mechanical barrier contributes to the pathogenesis of inflammatory bowel disease (IBD) and irradiation-induced intestinal injury (IRIII), both of which lack sufficient medical countermeasures currently. Reshaping the gut microbiota to increase the short-chain fatty acid (SCFA) levels is instrumental for fortifying the mechanical barrier and mitigating these diseases. Inspired by the fact that supplementation of essential trace elements selenium (Se) and cobalt (Co) can enrich SCFA-producing bacteria and promote microbial fermentation, respectively, we prepared tricobalt tetraselenide nanoparticles (Co₃Se₄ NPs) using a facile biomineralization approach in this study. Oral Co₃Se₄ NP administration increased intestinal microbial diversity and enriched <i>Alloprevotella</i>, which produced SCFAs, particularly butyric acid (BA), in the gut. Further investigation revealed that BA activated the cell-surface G-protein-coupled receptor 43 (GPR43) in enterocytes and induced protein kinase B (AKT) phosphorylation, resulting in increased expression of the tight junction (TJ) proteins occludin and zonula occludens-1. Accordingly, Co₃Se₄ NPs ameliorated the gut microbiota dysbiosis and TJ disruption caused by dextran sulfate sodium salt (DSS) and total abdominal γ-ray irradiation, producing a fortified mechanical barrier and alleviating DSS-induced colitis and IRIII in mice. This study demonstrated a biocompatible nanomaterial that can reshape the gut microbiota and fortify epithelial TJs, thereby providing an effective strategy for IBD and IRIII therapies.