BACKGROUND In mice, immunological adaptation of the gut to microbial and nutritional antigens occurs at weaning in parallel with biochemical and morphological maturation. Because oral administration of spermine to neonatal rats has been shown to induce biochemical and morphological maturation, we investigated whether spermine also affects maturation of the mucosal immune system. METHODS Swiss mice 7, 12, and 27 days old were given spermine orally (0.5 mumol/g body weight) during 3 days. Intestinal length was measured, and lactase and sucrase activities were determined. The phenotype of intraepithelial and lamina propria lymphocytes was assessed by FACS analysis using markers for CD3, TCR alpha beta, TCR gamma delta, CD4, CD8 alpha, CD8 beta, CD5, CD18, CD54, and CD49d. RESULTS Similar to what occurs during natural development, spermine treatment of neonatal mice increased intestinal length, decreased lactase activity, and increased sucrase activity. The percentage of intraepithelial lymphocytes expressing TCR alpha beta, CD4, CD5, and CD54, as well as the levels of expression of these antigens, increased after spermine treatment on day 12, similarly to natural maturation. The increase in expression of CD3, TCR gamma delta, CD18, and CD49d did not reach statistical significance. No effect was observed on CD8 expression. The phenotype of lamina propria lymphocytes was not affected. Spermine administration to 7- and 27-day-old mice had no effect on the phenotype of either intraepithelial or lamina propria lymphocytes. CONCLUSIONS Oral spermine administration to neonatal mice induced, in parallel with biochemical maturation, precocious maturation of the murine intestinal immune system and particularly affected differentiation of the intraepithelial lymphocyte population.