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The health benefits of breast-feeding have been recognised for a long time. In particular, breast-feeding is associated with lower incidence of necrotising enterocolitis and diarrhoea during the early period of life and with lower incidence of inflammatory bowel diseases, type 2 diabetes and obesity later in life. The higher nutritional and protective degree of human milk is related to its nutritional composition that changes over the lactation period and to the biological activities of specific components while lower growth rate of breast-fed infants may be attributed to their self-regulation of milk intake at a lower level than formula-fed infants. Many results now suggest that the developmental changes in intestinal and pancreatic function that occur postnatally are modulated by the diet. Indeed, formula-feeding induces intestinal hypertrophy and accelerates maturation of hydrolysis capacities; it increases intestinal permeability and bacterial translocation, but does not induce evident differences in microbiota composition. Whether these changes would be beneficial for enhancing absorptive capacities and for educating the gut-associated immune system remains to be further studied. Moreover, it is evident that formula-feeding increases basal blood glucose and decreases plasma ketone body concentrations, while discrepancies on postprandial glycaemia, insulin and incretin responses in both human studies and experimental studies are inconclusive. Manipulating the composition of formula, by reducing protein content, adding prebiotics, growth factors or secretory IgA can modulate intestinal and pancreatic function development, and thereby may reduce the differential responses between breast-fed and formula-fed neonates. However, the developmental responses of the digestive tract to different feeding strategies must be elucidated in terms of sensitivity to developing diseases, taking into account the major role of the intestinal microbiota.