Background and aims Preterm birth predisposes to neurological sequelae. Necrotizing enterocolitis (NEC) may further increase the susceptibility to neurological damage, possibly via gut-derived inflammatory signals. To investigate this, we test if NEC severity and intestinal permeability in formula-fed preterm pigs is associated with histopathology, microglial activation, and increased proinflammatory cytokine levels in the hippocampus.
Methods Forty-four preterm piglets were fed increasing doses of formula and euthanized on day five. Macroscopic NEC lesions were scored in five regions of the gut (stomach, proximal, middle, and distal small intestine, colon). Intestinal permeability was assessed by urinary lactulose-mannitol-ratio. Hippocampal IL-1β and IL-8 levels were determined by ELISA. Histopathology, neurodegeneration, and microglia were investigated by analyses of hematoxylin-eosin, Fluoro-jade B (FJB), and Iba-1 stained coronal sections, respectively.
Results Proximal, middle, and distal small intestinal NEC score, and intestinal permeability correlated positively with IL-8 levels (all p < 0.05) but not with IL-1β. In preterm piglets with severe NEC lesions, numerous shrunken, hyperchromatic neurons were observed. Neurodegeneration was confirmed by positive FJB staining. Iba-1 positive cells with a morphology resembling activated microglia populated the area in which neurons had disappeared.
Conclusions Acute development of NEC is associated with neuron loss, microglial activation, and increased IL-8 levels in the hippocampus of preterm pigs. Gut inflammatory disorders and increased intestinal permeability may affect the immature brain and contribute to long term neurological disorders.