Dysmotility Increases Late Onset Sepsis-like Disease Risk in Neonatal Mice

Background: Almost 75% of extremely premature infants experience feeding intolerance, a condition marked by a non-specific symptoms including abdominal distension and emesis. Immature intestinal dysmotility contributes to feeding tolerance in these patients. While many cases are benign, feeding intolerance can be a harbinger of potentially lethal complications of prematurity of necrotizing enterocolitis (NEC). Recent studies have demonstrated that motility is a modifiable risk factor for NEC severity in mouse models.

Objectives: Late onset sepsis (LOS) is commonly caused by translocation of bacteria from the gut lumen into the blood stream. It is currently unknown how intestinal motility contributes to neonatal sepsis risk. We hypothesize that impaired motility will increase the risk of bacterial translocation and susceptibility to LOS-like disease in neonatal mice.

Design/Methods: Neonatal mice were treated with 10mg/kg of vehicle, loperamide, or metoclopramide by mouth daily from day of life (DOL) 4 until assessment. Mice found to be losing weight or moribund were sacrificed per animal protocol specifications. For translocation experiments, mice were sacrificed on DOL 9 and spleen, liver, and mesenteric lymph node (MLN) were isolated, homogenized and plated on LB Agar plates

Results: To determine how impaired motility impacts survival in neonatal mice, pups were treated with vehicle or loperamide daily starting on DOL 4. Mice were assessed daily through DOL 19 evaluate survival. Loperamide treated mice had significantly impaired survival to DOL 19 compared to mice treated to vehicle alone (Vehicle - 85% survival, median survival undefined n=20, Loperamide - 47.1% , DOL 18 median survival n=17, p=0.022 Mantel-Cox Test). We next assessed if impaired motility affected bacterial translocation to from the gastrointestinal lumen to the spleen, liver, MLN. Loperamide treated mice are significantly more likely to have bacterial translocation to the MLN compared to controls (control 33% n=9, loperamide 64% n=11, p=0.008, binomial distribution). There was no statistical difference in translocation to the liver or spleen between loperamide-treated and control DOL9 pups.

Conclusions: Impaired motility increases the risk of death due to LOS-like disease in neonatal mice. Future directions will focus on the mechanisms by which bacteria breach the intestinal barrier as well as characterizing the bacteria that translocate systemically in loperamide-treated pups.