Necrotizing 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.
Mucosal intestinal injury consistent with human NEC was induced in P14-16 mice by disrupting Paneth cells, followed by gavage of Klebsiella pneumonia. Mucosal injury was determined by histology, serum cytokine levels, and epithelial barrier dysfunction. 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.
Live bacteria were required to induce injury, however TLR4 activation was not required. Paneth cell disruption-induced NEC induces altered localization of tight junction proteins and subsequent loss of barrier function.
Prior research has shown a requirement of TLR4 activation to induce NEC-like damage. However, many infants develop NEC in the absence of Gram negative rod bacteremia raising the question of alternate pathways to intestinal injury. In this data, we show a novel mechanism for development of intestinal injury equivalent to that seen in human NEC and 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.
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 August 2020.
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