Neurologic Consequences of Neonatal Necrotizing Enterocolitis

Berken, Jonathan A.; Chang, Jill

doi:10.1159/000525378

Cited by 16 publications

(12 citation statements)

References 121 publications

(195 reference statements)

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“…The presence of neurological changes and subsequent NDI in patients with a history of NEC is well established ( 13 , 14 ). The systemic inflammatory response triggered by NEC may be mediated via bacterial products and cytokines released during intestinal injury.…”

Section: Neurological and Developmental Delay Seen In Necmentioning

confidence: 99%

“…Other neural changes noted include alterations of the brain parenchyma, decreased head circumference, and corresponding decreased volumes in total brain matter ( 16 , 17 ). This stunted head growth and altered brain parenchyma in early infancy are detrimental to later cognitive outcomes and result in downstream NDI including: a higher incidence of cerebral palsy(CP), impaired motor function, visual and hearing impairment, and cognitive deficits ( 14 , 16 , 17 ).…”

Section: Neurological and Developmental Delay Seen In Necmentioning

confidence: 99%

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Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

Manohar

Mesfin²,

Liu³

et al. 2023

Front. Pediatr.

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Necrotizing enterocolitis (NEC) is a devastating condition of multi-factorial origin that affects the intestine of premature infants and results in high morbidity and mortality. Infants that survive contend with several long-term sequelae including neurodevelopmental impairment (NDI)—which encompasses cognitive and psychosocial deficits as well as motor, vision, and hearing impairment. Alterations in the gut-brain axis (GBA) homeostasis have been implicated in the pathogenesis of NEC and the development of NDI. The crosstalk along the GBA suggests that microbial dysbiosis and subsequent bowel injury can initiate systemic inflammation which is followed by pathogenic signaling cascades with multiple pathways that ultimately lead to the brain. These signals reach the brain and activate an inflammatory cascade in the brain resulting in white matter injury, impaired myelination, delayed head growth, and eventual downstream NDI. The purpose of this review is to summarize the NDI seen in NEC, discuss what is known about the GBA, explore the relationship between the GBA and perinatal brain injury in the setting of NEC, and finally, highlight the existing research into possible therapies to help prevent these deleterious outcomes.

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Section: Neurological and Developmental Delay Seen In Necmentioning

confidence: 99%

Section: Neurological and Developmental Delay Seen In Necmentioning

confidence: 99%

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

Manohar

Mesfin²,

Liu³

et al. 2023

Front. Pediatr.

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“…Pro- and anti-inflammatory cytokines have early and late phase components; early phase cytokines such as TNF-α may already be declining when measured in the brain in our NEC model. Alternately, the blood brain barrier may filter circulating cytokines and chemokines and limit the number of cytokines activating neuroinflammation [28]. The brain is a heterogenous organ, so specific regions may have cytokine and chemokine levels below the limit of detection by our methods.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, we observed that higher concentrations of DSS resulted in worsening clinical signs, intestinal pathology, and diminished intestinal cell proliferation. NEC causes local intestinal inflammation accompanied by cytokine and chemokine production that propagates to a systemic response [28]. We therefore measured cytokine and chemokine levels in the liver to determine if the levels of these inflammatory mediators correlate with the DSS concentration and the severity of enterocolitis.…”

Section: Higher Dss Concentrations In Feeds Led To Hepatic and System...mentioning

confidence: 99%

A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression

Sha,

Van Brunt,

Kudria

et al. 2023

Preprint

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Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal process that afflicts nearly 10% of premature babies born in the United States each year, with a mortality rate of 15-30%. NEC severity is graded using the Bells classification system based on the presenting symptoms and radiological findings. Animal models are a valuable tool in studying the pathogenesis of this disease; however, prior models cannot control the severity of NEC induced, a critical aspect of the disease in human infants. Here, we aim to bridge this gap in knowledge through development of a murine model of NEC with graded characteristics. Postnatal day 3 (P3) C57BL/6 mice were fed formula containing different concentrations (0.25%, 1%, 2%, and 3%) of dextran sodium sulfate (DSS), an osmotic agent previously shown to induce severe NEC in neonatal mice. P3 mice were fed every 3 hours over a 72-hour period. During feeding, we collected data on weight gain and behavior, which included activity, response, and body color. After feeding, at P6, we dissected the mice to check for bowel features and collect organs for immunohistochemistry and cytokine analysis. Mice fed formula only or 0% DSS were used as a control instead of breastfed mice. Since staying with the dam during the first week of life is vital to normal development in mice, using formula-fed mice as the control accounts for the handling bias that exists during feeding. Comparing breastfed and formula-fed mice alone, weight gain was significantly greater in breastfed mice, and liver cytokine concentrations tended to be higher. In the established graded NEC model, clinical differences were seen among the mice fed different DSS concentrations. Over the course of NEC induction, mice fed higher concentrations of DSS lost weight quicker and exhibited greater clinical severity scores. External bowel scores (dilation, color, and friability) were considerably worse in mice fed higher DSS concentrations; although internal small bowel pathology showed intestinal disarray among mice fed all DSS concentrations. Staining for cellular proliferation marker Ki-67 in intestines shows that mice fed higher concentrations of DSS display less cell proliferation at the base of the small intestine crypts. Pro-inflammatory cytokine levels in the liver, to assess systemic inflammation downstream of the gastrointestinal system, trended higher in mice fed with higher concentrations of DSS. Here, we demonstrate that we have successfully characterized a graded newborn mouse model where NEC severity can be predictably induced. This mouse model will be a valuable tool in gaining greater insight and understanding of the pathophysiology of this devastating disease process and to understand its long-term complications, such as neurodevelopmental impairment.

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“…According to the multicenter studies, the incidence rate of NEC in preterm infants is reported to be 3–12% ( Eaton, 2017 ; Meister et al, 2020 ; Cao et al, 2021 ) and the mortality is 9.4–17.6% ( D'Apremont et al, 2020 ; Cao et al, 2022 ; Xu et al, 2022 ) and can be much higher in those requiring surgeries ( Geng et al, 2018 ; D'Apremont et al, 2020 ). Moreover, among survivors, complications such as intestinal stricture, short bowel syndrome and delayed neurological development seriously affect their quality of life ( Frost et al, 2017 ; Berken and Chang, 2022 ). Therefore, early diagnosis of NEC will help decrease mortality and improve the outcome of NEC ( Neu, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Changes of gut microbiota and tricarboxylic acid metabolites may be helpful in early diagnosis of necrotizing enterocolitis: A pilot study

Liu

et al. 2023

Front. Microbiol.

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PurposeWe aimed to explore the value of gut microbiota and tricarboxylic acid (TCA) metabolites in early diagnosis of necrotizing enterocolitis (NEC) among infants with abdominal manifestations.MethodsThirty-two preterm infants with abdominal manifestations at gestational age ≤ 34 weeks were included in the study and were divided into non-NEC (n = 16) and NEC (n = 16) groups. Faecal samples were collected when the infants were enrolled. The gut microbiota was analysed with high-throughput sequencing, and TCA metabolites were measured with multiple reaction monitoring (MRM) targeted metabolomics. Receiver operating characteristic (ROC) curves were generated to explore the predictive value of the obtained data.ResultsThere was no significant difference in alpha diversity or beta diversity between the two groups (p > 0.05). At the phylum level, Proteobacteria increased, and Actinomycetota decreased in the NEC group (p < 0.05). At the genus level, Bifidobacterium and Lactobacillaceae decreased significantly, and at the species level, unclassified Staphylococcus, Lactobacillaceae and Bifidobacterium animalis subsp. lactis decreased in the NEC group (p < 0.05). Further Linear discriminant analysis effect sizes (LEfSe) analysis showed that the change in Proteobacteria at the phylum level and Lactobacillaceae and Bifidobacterium at the genus level scored higher than 4. The concentrations of succinate, L-malic acid and oxaloacetate in the NEC group significantly increased (p < 0.05), and the areas under the ROC curve for these metabolites were 0.6641, 0.7617, and 0.7344, respectively.ConclusionDecreased unclassified Staphylococcus, Lactobacillaceae and Bifidobacterium animalis subsp. lactis at the species level as well as the increase in the contents of some TCA metabolites, including succinate, L-malic acid and oxaloacetate, have potential value for the early diagnosis of NEC.

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Neurologic Consequences of Neonatal Necrotizing Enterocolitis

Cited by 16 publications

References 121 publications

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression

Changes of gut microbiota and tricarboxylic acid metabolites may be helpful in early diagnosis of necrotizing enterocolitis: A pilot study

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