Human breast-milk feeding enhances the humoral and cell-mediated immune response in neonatal piglets

Authors: MIKLAVCIC, JOHN - Arkansas Children'S Nutrition Research Center (ACNC); Badger, Thomas; BOWLIN, ANNE - Arkansas Children'S Nutrition Research Center (ACNC); MATAZEL, KATELIN - Arkansas Children'S Nutrition Research Center (ACNC); CLEVES, MARIO - Arkansas Children'S Nutrition Research Center (ACNC); LEROITH, TANYA - Virginia Polytechnic Institution & State University; SARAF, MANISH - Arkansas Children'S Nutrition Research Center (ACNC); CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC); PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC); SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC); YERUVA, LAXMI - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/2/2018
Publication Date: 9/22/2018
Citation: Miklavcic, J.J., Badger, T.M., Bowlin, A.K., Matazel, K.S., Cleves, M.A., Leroith, T., Saraf, M.K., Chintapalli, S.V., Piccolo, B.D., Shankar, K., Yeruva, L. 2018. Human breast-milk feeding enhances the humoral and cell-mediated immune response in neonatal piglets. Journal of Nutrition. 148:1-11. https://doi.org/10.1093/jn/nxy170.
DOI: https://doi.org/10.1093/jn/nxy170

Interpretive Summary: The benefits of breastfeeding infants are well-characterized, including those on the immune system. However, determining the mechanism by which human breast milk (HBM) elicits effects on immune response requires investigation in an appropriate animal model. The purpose of this study was to determine the effects of postnatal diet on the development of immune cell-mediated activity and humoral immunity (the natural ability to raise antibodies), utilizing a novel model of HBM feeding in piglets. We believe this is the first use of HMB in a pig model and the first head-to-head comparison of human breast milk (HBM) and a commercial infant formula effects on the immune system. The results indicate that humoral and cell-mediated immune responses are significantly greater in HBM-fed than milk formula-fed piglets, suggesting that formula feeding may suppress experimentally-induced immune responses. We also observed natural gut milieu (intestinal microbiota, the normal population of bacteria in the gut) differences in HBM versus formula fed piglets. The influence of postnatal diet on intestinal microbiota composition constitutes a plausible and likely mechanism by which HBM confers beneficial effects on development of the local gut and systemic immune response. The present study controlled for feeding conditions and environment, allowing for differences in immune outcomes and gut microbial colonization and growth to be attributed specifically to postnatal diet. Therefore, the porcine model of HBM-feeding employed in the current study is novel because it controls for these challenges and may be particularly relevant to studying the effects of diet and microbiome on immune response in the neonatal period. The studies provide evidence for a positive effect of breastfeeding on immune system development, and highlight that the HBM-fed piglet model may be useful in future studies comparing new formula options that better support immune health.

Technical Abstract: The benefits of breastfeeding infants are well characterized, including those on the immune system. However, determining the mechanism by which human breast milk (HBM) elicits effects on immune response requires investigation in an appropriate animal model. The primary aim of this study was to develop a novel porcine model and to determine the differential effects of feeding HBM and a commercial milk formula (MF) on immune response and gastrointestinal microbial colonization in a controlled environment. Male piglets were fed HBM (n = 26) or MF (n = 26) from day 2 through day 21. Piglets were vaccinated (n = 9/diet group) with cholera toxin and cholera toxin subunit B (CTB) and tetanus toxoid at 21 d or were fed placebo (n = 6/diet group) and then weaned to a standard solid diet at the age of 21 d. Humoral and cell-mediated immune responses were assessed from blood on days 35 and 48. Immune response was further examined from tissues, including mesenteric lymph nodes (MLNs), Peyer’s patches (PPs), and spleen. The colonization of gut microbiota was characterized from feces on days 16 and 49. Serum antibody titers in piglets fed HBM were 4-fold higher (P < 0.05) to CTB and 3-fold higher (P < 0.05) to tetanus toxoid compared with piglets fed MF on day 48. Compared with MF, the numbers of immunoglobulin A antibody–producing cells to CTB were 13-fold higher (P < 0.05) in MLNs and 11-fold higher (P < 0.05) in PPs in the HBM diet group on day 51. In addition, significantly increased T cell proliferation was observed in the HBM group relative to the MF group. Furthermore, microbial diversity in the HBM group was lower (P < 0.05) than in the MF group. This porcine model appears to be valid for studying the effects of early postnatal diet on immune responses and the gastrointestinal microbiome. Our results lay the groundwork for future studies defining the role of infant diet on microbiota and immune function.