Human milk is generally recognized as the gold stallion in neonatal nutrition. Structure, composition and physiological properties of Human milk are better mimicked in infant formulas that include milk lipids and milk fat membrane extracts although very few infant formulae use milk lipids more expensive than vegetable lipids. Two formulas based on i) vegetable fat (STD) or ii) a blend of vegetable fat and milk lipids stabilized by milk fat membrane extracts (EXP) were distributed with an automatic milk feeder to piglets from birth until 28 days. After euthanasia, Intestinal contents and tissues (proximal jejunum and ileum) and mesenteric lymph nodes (MLN) were collected. The residual immunoreactivity of β-lactoglobulin (β-lg) and caseins (Cns) present in the digestive compartments was determined by ELISA. The paracellular permeability (using FITC-dextran 4000) was evaluated using Ussing chambers. The EXP formula enhanced the resistance to proteolysis of β-lg and Cns. It modified microbiota with an increase in proteobacteria and a decrease in firmicutes. Ileal density (g/cm) was greater in EXP-fed piglets at 28 d. A decreased jejunal permeability was observed between d7 and d28 in EXP-fed piglets which was not observed with STD. There was an important effect of formula components on the secretory activity of MLN: a major immunosuppressor effect of the lipid fraction extracted from digestas of both formulas was evidenced. In conclusion, the lipid composition in infant formulas influenced the neonatal intestinal physiology through release of immunomodulatory lipids, modulation of proteolysis and modification of progressive colonisation of the infant digestive tract by bacteria.