Lysosomal overloading and necrotizing enterocolitis

Pediatr Surg Int. 2020 Oct;36(10):1157-1165. doi: 10.1007/s00383-020-04724-x. Epub 2020 Aug 1.


Purpose: Intestinal absorption in premature infants occurs via direct epithelial cellular endocytosis and degradation by intracellular lysosomes. Autophagy is a mechanism by which cytoplasmic organelles contribute to lysosomal degradation. However, excessive autophagy can lead to cell death. The purpose of this study was to investigate whether autophagy and endocytosis are present in the small intestinal mucosa during experimental necrotizing enterocolitis (NEC).

Methods: NEC was induced by gavage feeding of hyperosmolar formula, lipopolysaccharide and hypoxia between P5 and P9 (ethical approval 44032). Breastfed mice were used as control. Distal ileum was harvested on P5, P7 and P9 and analyzed for intestinal epithelial cellular morphology as well as autophagy/lysosomal activity, and cell death. Groups were compared using Student's t test.

Results: During NEC, giant lysosomes were present in the intestinal villi, with some exceeding their degradation ability leading to their rupture. The NEC group had significantly increased inflammation and autophagy activity, decreased lysosome activity, and increased apoptosis compared to control.

Conclusions: NEC induction causes excessive autophagy and endocytosis leading to lysosomal overloading, lysosomal membrane permeabilization and rupture which results in cell death. These novel findings may help to clarify the pathogenesis of NEC. Reduction of lysosome overload and assisting in their degradation capability may reduce the burden of NEC.

Keywords: Autophagy; Endocytosis; Lysosomal membrane permeabilization; Necrotizing enterocolitis.

MeSH terms

  • Animals
  • Animals, Newborn
  • Autophagy
  • Disease Models, Animal
  • Enterocolitis, Necrotizing / metabolism
  • Enterocolitis, Necrotizing / pathology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Ileum / pathology*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology*
  • Lysosomes / metabolism
  • Lysosomes / pathology*
  • Mice
  • Mice, Inbred C57BL