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.
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