Fat composition in infant formula contributes to the severity of necrotising enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is a devastating disease that typically affects formula-fed premature infants, suggesting that dietary components may influence disease pathogenesis. Triglycerides are the major fat component of infant formula, and their digestion requires pancreatic lipases, which may be naturally deficient in premature neonates. We hypothesize that NEC develops in part from the accumulation of incompletely digested long chain triglyceride-containing unsaturated fatty acids within the intestinal epithelial cells, leading to oxidative stress and enterocyte damage. We further hypothesize that the administration of a formula that contains reduced triglycerides (“pre-digested fats”) that don’t require lipase action may reduce NEC severity. To test these hypotheses, we induced NEC in neonatal mice using three different fat formulations, namely “standard fat”, “pre-digested fat”, or “very low fat”, and determined that mice fed “standard fat” developed severe NEC, which was significantly reduced in mice fed “pre-digested fat” or “very low fat”. The expression level of the critical fat digesting enzyme carboxyl-ester lipase was significantly lower in the newborn compared to older pups, leading to impaired fat digestion. The accumulation of mal-digested fat resulted in the dramatic accumulation of fat droplets within the intestinal epithelium of the distal ileum, resulting in the generation of reactive oxygen species and intestinal inflammation. Strikingly, these changes were prevented in pups fed “predigested fat” or “very low fat” formulas. These findings suggest that nutritional formula containing a predigested fat system may overcome the natural lipase deficiency of the premature gut, and serve as a novel approach to prevent NEC.

Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis

“…1d, e). Next, to determine whether maternal AHR activation could prevent NEC, we administered either I3C or a control diet that lacked I3C to mice during both pregnancy and lactation, and then induced NEC in the pups using a well-validated model 22,23 that closely mimics the human disease (see Methods). As shown in Fig.…”

“…Induction of NEC in mice. Experimental NEC was induced in a well validated and reproducible model in 7-day-old mice of either gender, which were randomly divided into control and test groups 22,23,27 , by gavage feeding newborn mice with formula containing Similac Advance infant formula (Abbott Nutrition): Esbilac (PetAg) canine milk replacer, 2:1 ratio, which was supplemented with enteric bacteria made from a stock created from a specimen obtained from an infant with surgical NEC five times per day. Additionally, the mice were subjected to hypoxia (5% O 2 -95% N 2 ) for 10 min in a hypoxia chamber (Billups-Rothenberg) twice daily for 4 days.…”

The human milk oligosaccharides 2’-fucosyllactose and 6’-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling

“…Experimental NEC was induced in 7–8 day old (approximately 3g body weight) neonatal mice pups as previously described and validated ( 17 ). NEC was induced after the oral gavage of formula which is described in our recent paper ( 18 ), and is composed of Similac Advance: Esbilac Canine Milk Replacer in equal concentrations, supplemented with bacterial stock that had been cultured from the stool of an infant with severe NEC (12.5μl of stool slurry in 1ml of formula). Neonatal pups were gavage-fed (50μl/g) five times per day with formula supplemented with bacterial using a 24-French angiocatheter placed into the mouse esophagus.…”

Proline-Rich Acidic Protein 1 (PRAP1) Protects the Gastrointestinal Epithelium From Irradiation-Induced Apoptosis

“… 27 Importantly, these stressors have the potential to significantly increase with a change in diet or gastrointestinal infection. 28 , 29 , 30 Discovering proteins critical to the epithelial response to oxidative insult has the potential to identify therapeutic targets to prevent tissue damage that ultimately results in a leaky gut phenotype. This occurs after the breakdown of the epithelial barrier of the gastrointestinal tract, increasing translocation of luminal antigens, microbes, and their products, which leads to increased local and systemic inflammation.…”