SEARCHNARRATIVE_REVIEWpediatrics, gastroenterology

narrative_review·pediatrics, gastroenterology, neurology, preclinical research, biomedical research·PMC10330774

New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics

Seminars in pediatric surgery · 3 authors, 1 centre

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TL;DR

This narrative review summarizes preclinical evidence that Toll-like receptor 4 (TLR4) activation by dysbiotic microbes and impaired intestinal motility drive the pathogenesis of necrotizing enterocolitis (NEC) in premature infants. The central result is that inhibition of TLR4 and strategies to enhance intestinal motility or limit neuroinflammation show therapeutic potential in preclinical models.

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This narrative review synthesizes preclinical and translational research on NEC pathogenesis, focusing on the role of TLR4 signaling in the premature gut. The authors describe a model where TLR4 activation by intestinal dysbiosis leads to exaggerated inflammation, mucosal injury, microvasculature vasoconstriction, and loss of enteric glia, causing intestinal damage. They report that impaired intestinal motility contributes to disease and that enhancing motility can reverse NEC in preclinical models. Implications include the rationale for developing small molecules to reduce NEC severity. The discussion is based on laboratory and animal studies, with direct human clinical evidence not reported.

STUDY TYPE

narrative_review

SPECIALTY

pediatrics

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AI pipeline

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100% · A

ORIGINAL PAPER

PMC10330774

New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics

Seminars in pediatric surgery

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ABSTRACT

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder in premature infants that causes significant morbidity and mortality. Research efforts into the pathogenesis of NEC have discovered a pivotal role for the gram-negative bacterial receptor, Toll-like receptor 4 (TLR4), in its development. TLR4 is activated by dysbiotic microbes within the intestinal lumen, which leads to an exaggerated inflammatory response within the developing intestine, resulting in mucosal injury. More recently, studies have identified that the impaired intestinal motility that occurs early in NEC has a causative role in disease development, as strategies to enhance intestinal motility can reverse NEC in preclinical models. There has also been broad appreciation that NEC also contributes to significant neuroinflammation, which we have linked to the effects of gut-derived pro-inflammatory molecules and immune cells which activate microglia in the developing brain, resulting in white matter injury. These findings suggest that the management of the intestinal inflammation may secondarily be neuroprotective. Importantly, despite the significant burden of NEC on premature infants, these and other studies have provided a strong rationale for the development of small molecules with the capability of reducing NEC severity in pre-clinical models, thus guiding the development of specific anti-NEC therapies. This review summarizes the roles of TLR4 signaling in the premature gut in the pathogenesis of NEC, and provides insights into optimal clinical management strategies based upon findings from laboratory studies.

CITATION EXPORT

Daniel J. Scheese, Chhinder P. Sodhi, David J. Hackam. New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics. Seminars in pediatric surgery. (2023). https://doi.org/10.1016/j.sempedsurg.2023.151309

AUTHORS

3 · 1 CENTRES

Daniel J. Scheese, Chhinder P. Sodhi, David J. Hackam

1Division of Pediatric Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA