Abstract
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.