Background and aim Studies in premature infants and animals show that carbohydrate malabsorption and gut microbiota colonisation are key elements for triggering necrotizing enterocolitis (NEC). Our aim was to determine how dietary carbohydrate composition affects the metabolomic profile and whether unique metabolite signatures correlate with NEC incidence.

Methods Cecal contents and plasma were collected from a group of preterm pigs at birth and from three groups fed formula containing either lactose, corn syrup solids (CSS) or a 1:1 mixture of lactose:CSS (MIX) as the sole carbohydrate. We performed metabolomic analysis by LC/GC mass spectroscopy, clinical and histological NEC scoring, and distal ileum tissue expression of inflammatory markers.

Results Based on clinical and histological scores NEC incidence rates were 12%, 35%, and 40% in the lactose, CSS and MIX groups, respectively. Ileum inflammatory markers (IL-8, IL-6, and IL1b) were highest in CSS vs. MIX and lactose groups and also correlated with NEC. Metabolomic analysis showed that lactose vs. CSS formula increased abundance of several cecal endocannabinoids. CSS and MIX formula increased plasma histamine, cecal and plasma lactate, beta-hydroxybutyrate, and butanediol, and decreased the abundance of several primary and secondary bile acids vs. lactose fed pigs.

Conclusions We conclude that lactose-based formula protects against inflammation and NEC and that this correlates with increased cecal levels of anti-inflammatory neurotransmitters and reduced levels of carbohydrate fermentation products and bile acids. This novel finding suggests that endocannabinoids, normally found in breast milk, may be produced endogenously and modulate inflammation in preterm neonates fed a lactose-based formula.