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A Digestive Cartridge Improves Survival and Reduces Intestinal Injury in a Murine Model of Necrotizing Enterocolitis
Sarah Z. Wang
1, Djanira Fernandes
1, Savas Tsikis
1, Thomas Hirsch
1, Scott Fligor
1, Amy Pan
1, Mikayla Quigley
1, Valeria Ruiz
1, Greta Loring
2, Stephen Davia
2, Carter Petty
1, Mark Puder
1
1. Surgery, Vascular Biology Program, Boston Children's Hospital, Boston, MA, United States. 2. Alcresta Therapeutics, Waltham, MA, United States.
Background: Formula feeding in premature infants is a risk factor for the development of necrotizing enterocolitis (NEC), a surgical emergency and the most common cause of short bowel syndrome in infants. Premature neonates are lipase-deficient, resulting in impaired fat digestion. The immobilized lipase cartridge (ILC) is an ex vivo enzymatic device that connects in-line with enteral feeding systems. The ILC hydrolyzes fat in enteral formula into readily absorbable free fatty acids prior to reaching the patient, and is FDA-approved for enteral nutrition support in children with fat malabsorption. We hypothesized that use of a new ILC prototype designed specifically for neonates will reduce mortality and disease severity in a murine NEC model.
Study Design: NEC was induced in C57BL/6J mouse pups via oral gavage of formula containing E. coli lipopolysaccharide (2.5 µg/g, 4x/day) and intermittent hypoxia (5% oxygen/95% nitrogen, 10 min 2x/day) from post-natal day (P) 4 through 6 (Figure 1). Littermates were randomized to one of three groups: breastmilk (dam-reared controls), NEC + undigested formula (placebo cartridge), and NEC + ILC-digested formula. Mortality and weights were measured daily. Two masked observers assessed established clinical sickness (0-12) and macroscopic gut appearance (0-6) scores on P7. Terminal ileum histology was evaluated for NEC severity by a masked certified veterinary pathologist. Statistical analysis was performed using analysis of variance (ANOVA), two-sample t-test, or log-rank test where applicable with values expressed as the mean ± standard error of mean.
Results: Normal controls had lower mortality than the NEC + Placebo and NEC + ILC groups (P<0.001) (Figure 2). Compared to the NEC +Placebo group, NEC mice fed ILC-digested formula had lower mortality (P=0.002), lower clinical sickness scores (4.1±0.5 v 6.7±0.5, P=0.004), and macroscopic gut scores (2.9±0.2 v 4.2±0.3, P=0.002). On representative histology, the NEC + ILC group had improved intestinal villus architecture compared to the NEC + Placebo group (Figure 3).
Conclusions: While breastmilk is the preferred food for infants, it is not universally available. Feeding with commercial formula increases the risk for NEC, particularly among premature infants who have under-developed gastrointestinal tracts and relative lipase deficiency. In a murine NEC model, administration of enteral formula pre-digested by the ILC improved survival, clinical sickness scores, macroscopic gut scores, and histologic severity of NEC. These findings support further investigation of the ILC as a non-invasive, preventative therapy for NEC in humans with the potential to reduce the need for operative intervention.
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