Mechanisms to explain how TLR4 activation in the premature intestinal epithelium is required in the pathogenesis of necrotizing enterocolitis. As shown, colonization of the intestine of the premature infant leads to the activation of TLR4 within the intestinal epithelium as well as on the intestinal stem cells, due in part to the elevated expression levels of TLR4 in the setting of prematurity. TLR4 activation leads to enterocyte apoptosis, impaired restitution and reduced proliferation as well as stem cell apoptosis, leading to bacterial translocation, systemic sepsis, and the development of NEC. See text for further details.