Gut Environmental Factors May Shape the Persistence of Faecalibacterium Prausnitzii in the Healthy and Diseased Large Intestine

Abstract

Background: Exposure to Helicobacter hepaticus, common enterohepatic bacteria, increases the incidence of experimental colitis and promotes colonic tumorigenesis. However, the role of H. hepaticus in pathogenesis of necrotizing enterocolitis (NEC) is not known. Neonatal NEC is a devastating disease of prematurely born babies. The cause of NEC is not clear, but inappropriate bacterial colonization plays an important role in NEC pathogenesis. Autophagy protects organisms against diverse pathologies, such as bacterial infections. However, uncontrolled activation of autophagy may lead to cellular injury. Aim: To test the effect of H. hepaticus on development of intestinal injury and expression of inflammatory and autophagic regulators in the rat model of NEC. Methods: Pregnant rats and newborn pups were kept either in H. hepaticus-free or in the H. hepaticus-contaminated environment. Prematurely born rat pups were hand-fed with formula and exposed to asphyxia/cold stress to develop NEC. After 96 hours, all animals were sacrificed and ileal tissue was collected. Incidence of NEC injury, expression of inflammatory cytokines (IL-6, IL-8, IL-18 & TNF-α) and protein levels of autophagy regulators (Beclin 1, LC3II & p62) were evaluated in the ileum. Results: Results: The incidence of NEC was significantly increased to 71% (25/35) in rats exposed to H. hepaticus compared with the H. hepaticus-free group with NEC incidence of 33% (13/39; p < 0.001). The survival rates were not affected by H. hepaticus. The presence of H. hepaticus was detected in the GI tract of the H. hepaticus group. IL-8 and IL-18 gene expression was significantly altered in the H. hepaticus group, whereas IL-6 and TNF-α levels were not changed. Protein levels of Beclin 1 and LC3II were markedly increased, whereas p62 levels were significantly decreased in the ileum from the H. hepaticus group. Conclusions: Helicobacter hepaticus exacerbates intestinal injury and induces intestinal inflammation in the rat NEC model. Exposure to H. hepaticus is also associated with a strong induction of the autophagy pathway in the site of injury the terminal ileum. Inappropriate activation of intestinal autophagy by bacterial insult may facilitate massive cell death, leading to severe mucosal injury. Supported by the NIH Grant HD-39657 (to B.D.)