Abstract
ABSTRACTNecrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in premature infants. Both human surgical specimens and animal models suggest a potential involvement of Paneth cells in NEC pathogenesis. Paneth cells play critical roles in epithelial homeostasis, innate immunity and host-microbial interactions. Yet, the complex interplay between Paneth cell disruption, epithelial barrier dysfunction and microbial-driven inflammation remains unclear in the immature intestine. In this study, mucosal intestinal injury consistent with human NEC was induced in postnatal day 14-16 (P14-P16) mice by disrupting Paneth cells, followed by gavage with Klebsiella pneumonia. Mucosal injury was determined by histology, serum cytokine levels and epithelial barrier dysfunction. Toll-like receptor 4 (TLR4) activation was examined using protein expression, gene expression, and TLR4−/− mice. Finally, the role of bacteria was evaluated using heat-killed bacteria, conditioned media, Bacillus cereus and cecal slurries. We found that live bacteria were required to induce injury; however, TLR4 activation was not required. NEC induced by Paneth cell disruption results in altered localization of tight junction proteins and subsequent loss of barrier function. Prior research has shown a requirement for TLR4 activation to induce NEC-like damage. However, many infants develop NEC in the absence of Gram-negative rod bacteremia, raising the possibility that alternative pathways to intestinal injury exist. In this study, we show a previously unknown mechanism for the development of intestinal injury equivalent to that seen in human NEC and that is not dependent on TLR4 pathways. These data are congruent with the new hypothesis that NEC may be the consequence of several disease processes ending in a final common inflammatory pathway.
Highlights
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease found almost exclusively in premature infants (Minino et al, 2002)
Paneth-cell-disruption-induced injury is similar to the pathophysiology seen in human NEC The Paneth-cell-disruption model of NEC was originally described in CD-1 mice (Zhang et al, 2012)
In addition to developing NEC-like injury that is specific to the distal small intestine (Fig. 1B), injury induced by Paneth cell disruption exhibits developmental dependence
Summary
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease found almost exclusively in premature infants (Minino et al, 2002). Received 14 November 2016; Accepted 7 April 2017 mechanism is supported by clinical signs of NEC. These include pneumatosis intestinalis [gas pockets within the bowel wall caused by bacterial fermentation (Hill et al, 1974)], epidemic episodes of NEC, and infant bacteremia or endotoxemia (Bizzarro et al, 2014). TLR4 activation is a key mechanism by which the host can detect and respond to the lipopolysaccharide contained in the cell wall of Gram-negative bacteria. Many infants develop disease without signs of Gram-negative invasion, raising the possibility of additional mechanisms to induce NEC
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