Necrotizing enterocolitis: Pathophysiology from a historical context
Section snippets
Historical perspective
Although not described as classic NEC, a report from almost 200 years ago by Charles Billard described a case from the Hopital Des Infants Trouves in Paris, France in which ‘a foundling newborn developed a swollen abdomen with greenish then bloody diarrhea, developing a tense abdomen, cold extremities, bradycardia, and subsequent death.’ The autopsy of this patient described an intensely red and swollen terminal ileum, with friable mucosa and the surface covered with blood. In fact, the mucosa
Enteral feedings in NEC pathogenesis
In the early 1970s, Dr. Barlow and colleagues in New York developed a newborn rat model of NEC that included formula feeding, intermittent asphyxia, and bacterial colonization.6 Initial studies demonstrated that rat mother’s milk feedings completely protected against NEC compared to newborn pups who received formula feedings, and it was hypothesized that breast milk feedings provided mucosal immunity that promoted colonization with commensal microbes thus allowing for normal mucosal epithelial
Effect of microbiome
It was suggested over 50 years ago that bacteria contributed significantly to the development of NEC. Mizrahi and colleagues in NYC cultured blood and peritoneal fluid from patients with disease and demonstrated a predilection for Gram negative bacteria, particularly Escherichia coli as offending agents associated with NEC.16 Additional studies in the early 1970s showed that ‘epidemics’ of NEC occurred in some NICU’s, and in one of the first reports, Stein et al.17 showed that Salmonella
Inflammation and NEC
For many years, the pathogenesis of NEC was thought to be multifactorial and occurred in response to several key risk factors of prematurity, enteral feeding, intestinal ischemia, and bacterial effects.25 In addition, it was suggested in the 1960s and 1970s that these risk factors stimulated an inflammatory response that either localized in the intestine, or could become more systemic in more severe cases of NEC. In early reports, it was suggested that bacterial products such as endotoxin (also
Impaired bacterial-enterocyte signaling provides a unifying theme to understand the pathogenesis of NEC
The above paragraphs provide a detailed historical perspective regarding the initial descriptions of NEC, and an evolution in our understanding of what causes this devastating disease in the first place. We have reviewed the initial presentation of this disease in neonates, described how animal models have been developed which mimic the disease, and have described various molecular factors that contribute to its pathogenesis. Importantly, the themes related to the diagnosis of NEC are
Bacterial signaling in the premature host leads to NEC
Several investigators have focused on elucidating the mechanisms by which bacterial signaling occurs in the premature host, and how abnormal bacterial signaling can lead to the development of NEC. One of the most exciting discoveries in this regard was the identification of the role of the Toll-like receptors as pathogen recognition molecules that allow the host to respond to potential pathogens – including bacteria – without ever having seen them before. The first family member identified –
Mechanisms of intestinal death in the pathogenesis of NEC
While the above findings explain the mechanisms by which bacterial intestinal signaling in the premature host may lead to inflammation as seen in NEC, additional findings explain the mechanisms that underlie the tissue death that is characteristic of this disease. Specifically, as noted above, TLR4-mediated bacterial signaling leads to increased mucosal injury and reduced mucosal repair, resulting in mucosal defects through which enteric organisms can readily translocate into the circulation in
Curtailing bacterial signaling in the premature intestine to prevent NEC: amniotic fluid, breast milk and probiotics
The above findings provide evidence that exaggerated bacterial signaling plays a role in the development of NEC in premature infants, and suggest the possibility that strategies may exist which curtail the degree of TLR4 signaling, and limit the propensity for NEC development. In this regard, several groups have shown that amniotic fluid administration can limit NEC,42, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 which Hackam et al. showed to be due to effects on inhibition of the degree of
Pharmacologic inhibition of TLR4 for the prevention and treatment of NEC
Having shown a critical role for bacterial signaling in the pathogenesis of NEC through activation of the LPS receptor TLR4, we and others have sought to identify whether pharmacologic inhibition of TLR4 may represent a novel approach for the prevention or treatment of NEC. To do so, the Hackam laboratory performed an in silico screen of potential binding partners to the LPS docking site within TLR4, based upon the recently published crystal structure of this molecule.70, 71 This screen yielded
Potential multi-agent approaches for NEC prevention and treatment
Based upon the above understanding of the role of bacterial signaling in the pathogenesis of NEC, a variety of potential molecular approaches could be proposed for the prevention or treatment of NEC, using a strategy of TLR4 inhibition. Such approaches may include inhibition of the upstream TLR4 signaling pathways using C34 or other novel and potentially more potent analogs, or the administration of probiotic bacteria or probiotic DNA, which serve to limit TLR4 activation via effects on TLR9.
Summary
Necrotizing enterocolitis has caused significant morbidity and mortality in neonatal units for many years, and the historical context provides an interesting variety of scientific insights. As the pathogenesis of NEC has become better understood, our recent findings on the role of bacterial signaling in the pathogenesis of NEC suggest possible answers to the questions posed above regarding the epidemiology of this disease. Specifically, it appears that the premature intestinal epithelium is at
Future considerations
Based in part on early successes in the understanding of the role of bacterial signaling in NEC pathogenesis, there is reason to be optimistic that the field of NEC research is poised to enter a period of significant advancement towards the ultimate goal of developing a specific cure for this disease. To accomplish this goal, we will need to understand with greater accuracy which patients are most susceptible to the development of NEC; this will likely require the identification of specific
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