Interactions of resident intestinal microbes with the luminal contents and the mucosal surface play important roles in normal intestinal development, nutrition, and innate and adaptive immunity. The neonate, especially the premature, who possesses a highly immunoreactive intestinal submucosa underlying a single layer of epithelial cells that are continuously exposed to the luminal environment, is highly susceptible to perturbations of the luminal environment. Understanding the interactions of the intestinal ecosystem with the host and luminal nutritional environment, especially in regard to human milk and pre- and probiotics, has major implications for the pathogenesis of diseases that affect not only the intestine but distal organs such as the lung and brain.