Ultra‐High Temperature Treatment and Storage of Infant Formula Induces Dietary Protein Modifications, Gut Dysfunction, and Inflammation in Preterm Pigs

Abstract

Scope: Ready-to-feed liquid infant formula is increasingly used for preterm infants when human milk is unavailable. These formulas are sterilized by ultra-high temperature treatment, but heating and storage may reduce bioactivity and increase formation of Maillard reaction products with potential negative consequences for immature newborns. Methods and results: Using preterm pigs as a model for sensitive newborn infants, the study tests the intestinal responses of feeding experimental liquid formula within 5 days. A pasteurized formula (PAST) with the same nutrient composition but less protein modifications serves as control to ultra-high temperature-treated formula without (UHT) and with prolonged storage (SUHT). Relative to PAST, UHT contains lower levels of lactoferrin and IgG. Additional storage (40 °C, 60 days, SUHT) reduces antimicrobial capacity and increases non-reducible protein aggregates and Maillard reaction products (up to 13-fold). Pigs fed SUHT have more diarrhea and show signs of intestinal inflammation (necrotizing enterocolitis) compared with pigs fed PAST and UHT. These clinical effects are accompanied by accumulation of Maillard reaction products, protein cross-links, and inflammatory responses in the gut. Conclusion: The results demonstrate that feeding UHT infant formulas, particularly after prolonged storage, adversely affects gut maturation and function in preterm pigs used as a model of preterm infants.

Ultra‐High Temperature Treatment of Liquid Infant Formula, Systemic Immunity, and Kidney Development in Preterm Neonates

“…The SUHT‐fed pigs showed 2‐folder higher levels of circulating inflammatory cytokines (TNF‐α, IL‐6) compared to pigs fed PAST, which implied an overall proinflammatory status that might be related to subclinical organ inflammation (e.g., gut and kidney). [ 29 ] Further, the total phagocytic capacity in these pigs was lower than in pigs fed PAST, mainly driven by lower neutrophil counts, and a similar trend was found in eosinophils. Neutrophils are the major innate cell subset and key effector of the neonatal innate immune defense, and the decreased neutrophil counts in SUHT could be explained by local inflammation, which would drag more neutrophil homing from the blood to the organs, including gut and kidney.…”

“…The negligible amounts of MRPs found in the circulation indicate that the differences in systemic immunity among the three groups are indirectly related to dietary MRP levels, probably via effects on the gut inflammatory status as previously described. [ 29 ]…”

“…Detailed procedures on experimental IF preparations and characterization, including nutritional composition, MRPs and amino acid induced cross‐link products, and physicochemical property, were described in the associated publications. [ 13,14,29 ] Briefly, the levels of the early MRP, furosine, and AGEs were up to 6.5‐ and 13‐fold higher in UHT and SUHT, respectively, compared to PAST. The α‐dicarbonyl compounds were two‐ to eight‐fold higher in UHT, and the amino acid cross links lysinoalanine (LAL) and lanthionine (LAN) were two‐ to five‐fold higher in SUHT than PAST (details are described in table 1 in Sun et al.…”

“…In preterm pigs, we previously demonstrated that feeding IF with high MRP content and reduced bioactivity leads to AGEs accumulation in the immature gut, impaired intestinal structure and function and more necrotizing enterocolitis. [ 29 ] In intrauterine growth‐restricted pigs, IF‐derived AGEs lead to long‐term inflammation in the kidneys. [ 30 ] The immature kidneys could be particularly sensitive to the detrimental effects of AGEs due to high blood perfusion.…”

“…Hence, blood leukocyte and immune responses, systemic inflammation, and kidney morphology and function were evaluated in newborn preterm pigs exposed to UHT‐treated liquid IF, with or without long‐term storage at ambient temperatures ( Figure 1 ). The current results represent a follow‐up analysis of blood and kidney from a study described in our previous work, [ 29 ] where more details on the experimental design and IF characterization are described.…”