2′-Fucosyllactose transactivates EGF receptor in intestinal epithelial cells for prevention of colitis in adulthood

Human milk oligosaccharides (HMOs) benefit growth in infancy. However, mechanisms underlying regulation of host cellular responses by HMOs remain largely unknown. We report that 2'-fucosyllactose (2'-FL), an abundant oligosaccharide in human milk, interacts with a metalloproteinase, ADAM17, on the cell surface and stimulates its catalytic activity for releasing membrane-bound heparin-binding (HB)-EGF, leading to transactivation of epidermal growth factor receptor (EGFR) in intestinal epithelial cells (IECs). Further, this direct effect of 2'-FL on IECs contributed to preserving tight junctions and attenuating apoptosis in response to proinflammatory cytokine and oxidative stress. Remarkably, 2'-FL treatment prevented colitis and maintained intestinal epithelial integrity during colonic injury and colitis in wild-type adult mice, which was mitigated in mice with deletion of EGFR in IECs. These findings reveal a molecular mechanism of the direct protection of intestinal epithelium by 2'-FL and discern this effect as an approach for the prevention of intestinal inflammation beyond the early life.