The food additive 4-hexylresorcinol impairs intestinal stem cell function and exacerbates inflammatory bowel disease in Drosophila melanogaster via suppression of mapk signaling pathway.

The global incidence of inflammatory bowel disease (IBD) is rising, an epidemiological trend strongly linked to the increasing consumption of ultra-processed foods. Although certain food additives are implicated in IBD pathogenesis, the direct impact of these additives on intestinal stem cells (ISCs), key effectors of epithelial homeostasis and repair, is poorly defined. Specifically, 4-hexylresorcinol (4-HR), a widely used phenolic preservative, has not been thoroughly investigated for its long-term impact on intestinal health, particularly during inflammation and repair. Using a Drosophila melanogaster model of bleomycin (BLM)-induced intestinal injury, we combined genetic analysis, immunofluorescence staining, and functional assays to evaluate the effects of 4-HR on tissue pathology, ISC proliferation, and evolutionarily conserved pro-repair signaling pathways. Our findings indicate that 4-HR significantly aggravates intestinal damage and impedes epithelial regeneration by suppressing the injury-induced proliferation of ISCs. Mechanistic studies revealed that 4-HR inhibits the activation of the MAPK signaling pathway, which is critical for initiating the reparative program following injury. Importantly, we extend these findings to a mammalian system, demonstrating that 4-HR similarly impairs intestinal repair and suppresses the conserved MAPK signaling axis in a mouse model of colitis. Collectively, our data elucidate a previously unrecognized mechanism whereby the food additive 4-HR aggravates intestinal damage and impedes epithelial regeneration by directly suppression MAPK-dependent, ISC-driven repair. This cross-species validation establishes the detrimental role of 4-HR and its core mechanism as conserved from invertebrates to mammals, not only establishing a novel link between dietary factors and epithelial repair dysregulation but also underscoring a significant dietary environmental contributor to IBD pathogenesis. Furthermore, this study establishes a foundation for future research into how dietary components influence stem-cell biology, underscoring the urgent need to re-evaluate the long-term safety of common food additives in vulnerable populations.