Dietary fiber deficiency exacerbates intestinal inflammation via miR-6240-enriched gut extracellular vesicles

Emerging evidence underscores the critical role of dietary fiber in maintaining gut homeostasis. While extracellular vesicles (EVs) have recently gained attention as key mediators of host-microbe communication, their functional contribution to fiber deficiency-associated pathologies remains largely unexplored. In this study, we revealed that a fiber-free diet induces significant intestinal inflammatory damage in mice, an effect that can be faithfully reproduced through fecal microbiota transplantation. Importantly, we demonstrated that intestinal epithelial cells-derived EVs from fiber-deprived mice are sufficient to recapitulate the detrimental effects of fiber deficiency. Mechanistic studies revealed enrichment of miR-6240 in these EVs, which targeted the 3'UTR of STAT6 mRNA to suppress its expression. This impairment of STAT6 signaling inhibited M2 macrophage polarization, exacerbating intestinal inflammation. This novel pathway is further validated in primary macrophage adoptive transfer experiments. Our work unveils a previously unrecognized mechanism by which fiber deficiency exacerbates intestinal inflammation through IECs-derived EVs and miR-6240/STAT6-mediated macrophage dysfunction.