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 postnatal day (PD) 10-12 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 immunoglobulins type G (IgG) transporter FcRn were reduced in the intestine of Prlr^-/- nursing pups. In summary, the 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.NEW & NOTEWORTHY Prolactin promotes lactation in the mother and is present in maternal milk; however, its effects on lactating pups have been overlooked. Our study shows that milk-derived prolactin acts on the intestine of mouse pups, maintaining the neonatal phenotype of the intestinal epithelium, preventing an accelerated transition to an adult-type epithelium. This process allows optimal utilization of nutrients and signals from maternal milk. These findings highlight the relevance of milk-borne maternal signals in regulating neonatal physiology.