Transactivation of EGF receptor in intestinal epithelial cells by 2’-fucosyllactose mediates prevention of colitis in adulthood

2’-fucosyllactose (2’-FL) is a unique oligosaccharide in human milk. We previously reported that 2’-FL protected intestinal integrity, modulated the gut microbial metabolism, and ameliorated intestinal inflammation in adult mice. This study aimed to elucidate mechanisms underlying the direct effects of 2’-FL on intestinal epithelial cells (IECs) for preventing colitis in adulthood. We found that 2’-FL transactivated EGFR in a colonic epithelial cell line, which required 2’-FL-stimulated release of HB-EGF from the cell membrane. Further, findings of 2’-FL-stimulated ADAM17 kinases activity on the cell surface and docking site of 2’-FL to the metalloprotease domain of ADAM17 suggest that 2’-FL could enhance ADAM17 shedding activity for releasing HB-EGF. Remarkably, apoptosis and disruption of tight junction induced by a proinflammatory cytokine and oxidative stress were mitigated by 2’-FL in wild-type, but not EGFR knock-out cell line and colonoids. By using the murine model of colonic injury and colitis induced by DSS, 2’-FL treatment prevented colitis, decreased epithelial apoptosis, and preserved intestinal barrier in wild-type adult mice. These effects were diminished in mice with EGFR deletion in IECs. This study demonstrates a novel mechanism underlying the direct transactivation of EGFR in IECs by 2’-FL that mediates protection of IECs during intestinal inflammation in adulthood.