Little is known about the role of oxytocin (OT) in colostrum during early gut colonization. We previously showed that transient OT receptor (OTR) expression on newborn rat enterocytes coincides with the milk-suckling period, and that OT activates endoplasmic reticulum stress sensors in cultured enterocytes. Here, we explored whether colostrum-OT attenuates stress in newborn villi primed and unprimed by colostrum by measuring levels of stress markers including BiP (an ER chaperone), elF2a (translation initiation factor), and pPKR (elF2a kinase). We also measured two inflammation-signaling proteins NF-kappa B and its inhibitor I kappa B. To test the impact of colostrum on autophagy, we measured a marker of autophagy initiation, LC3A. Colostrum increased inactive p-elF2a, p-PKR and I kappa B and reduced p-I kappa B, BiP and LC3A. LPS increased and OT decreased p-I kappa B. BiP (GRP78) was higher in unprimed than primed villi. Together, these data suggest that colostrum OT attenuates the impact of inflammation on postnatal gut villi and that OT enhances autophagy to protect against amino acid insufficiency-induced stress during the interval between birth and the first feeding. (C) 2017 Elsevier Inc. All rights reserved.