Prolactin maintains the neonatal phenotype of enterocytes during lactation in newborn mice.

After birth, the intestine experiences a gradual maturation process that transforms the gut epithelium to adapt to the changing feeding conditions, from maternal milk to solid food. Milk components regulate this transition from neonatal- to adult-type enterocytes. Prolactin (PRL), a hormone present in milk at high concentrations, regulates the metabolism of the nursing pups. However, the target tissues that mediate its actions are unknown. Here, we hypothesized that milk PRL influences the transition from neonatal- to adult-type enterocytes. We found that PRL and PRL receptors are present in the intestinal epithelium (IE) of neonatal mice where PRL exerts direct actions. PRL activated the AKT and ERK1/2 signaling pathways in intestinal epithelial cells in culture from PD10-12 neonatal mice, and spheroids derived from neonatal intestine proliferate in response to PRL. Moreover, at PD14, the intestine villi length, crypt depth and number are increased in PRL receptor null mice (Prlr^-/-), suggesting an accelerated maturation phenotype in the absence of PRL signaling. Also, Prlr^-/- mice showed decreased expression of neonatal IE markers and increased expression of adult-type IE markers. Consistently, the activity of lactase and the levels of the IgG transporter FcRn were reduced in the intestine of Prlr^-/- nursing pups. In summary, lack of PRL signaling promotes precocious intestinal enterocyte maturation, which may lead to adverse health consequences such as poor digestion of lactose and reduced passive immunity. By restraining intestinal maturation, PRL helps maintain the neonatal enterocyte phenotype needed to promote the optimal use of milk components in the nursing offspring.