Nutritional, microbiological and immunological dysfunctions all play a role in NEC etiology but the relationship among these determinants is not understood. The preterm gut is very sensitive to enteral feeding which may either promote gut adaptation or induce gut dysfunction via bacterial overgrowth and inflammatory reactions. Tumor necrosis factor alpha, toll-like receptors and heat-shock proteins are identified among the immunological components of the early mucosal dysfunction. It remains difficult, however, to distinguish the early initiators of NEC from the later consequences of the disease pathology. To elucidate the mechanisms and identify clinical interventions, animal models showing spontaneous NEC development may help. In this review, we summarize some recent results from studies on preterm pigs during the early feeding-induced mucosal dysfunction and later NEC development. We show that introduction of suboptimal enteral formula diets, coupled with parenteral nutrition, predispose to disease, while advancing amounts of mother’s milk from birth protects against disease. Hence, the transition from parenteral to enteral nutrition shortly after birth plays a pivotal role to secure gut growth, digestive maturation and an appropriate response to bacterial colonization in the sensitive gut of preterm neonates. Ongoing studies in preterm pigs aim to identify the optimal time, amount and diet of the first enteral milk that best secure both early gut adaptation and later body growth and health.