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. Author manuscript; available in PMC: 2025 Aug 16.
Published in final edited form as: Am J Perinatol. 2025 Mar 20;42(15):1947–1954. doi: 10.1055/a-2563-0878

Gut-Brain Axis in Preterm Infants with Surgical Necrotizing Enterocolitis

Parvesh Mohan Garg 1, Jeffrey S Shenberger 3, Mckenzie Ostrander 2, Terrie E Inder 4, Padma P Garg 2
PMCID: PMC12353609  NIHMSID: NIHMS2068100  PMID: 40112874

Abstract

Necrotizing enterocolitis (NEC) affects 5–10% of very-low-birth-weight infants and remains a leading cause of mortality and long-term morbidity. Preterm infants with NEC, especially those requiring surgery, have higher inflammatory markers in the blood, severe white matter abnormalities on brain imaging, and adverse neurodevelopmental outcomes. This review presents current evidence regarding the clinical factors associated with brain injury in preterm infants with necrotizing enterocolitis needing surgical intervention. Studies that evaluate neuroprotective strategies to prevent brain injury are greatly needed to improve neurodevelopmental outcomes in high-risk preterm infants with NEC.

Introduction:

Necrotizing enterocolitis (NEC) affects 5–10% of very-low-birth-weight infants and remains a leading cause of mortality and long-term morbidity [1]. The risk factors associated with NEC are complex and multifactorial [1]. A recent meta-analysis [2] has reported that the neurodevelopmental impairment (NDI) incidence was 40% (IQR 28%−64%) in infants with NEC. NDI was higher in infants with surgically treated NEC (43%) compared with medically managed NEC (27%, p<0.00001). The most common NDI in NEC was cerebral palsy (18%). Intraventricular hemorrhage (IVH) was more common in NEC babies (26%) compared with preterm infants (18%; p<0.0001). There was no difference in IVH incidence between infants with surgical NEC (25%) and those treated medically (20%; p=0.4). The incidence of periventricular leukomalacia (PVL) was significantly increased in infants with NEC (11%) compared with preterm infants (5%; p<0.00001) [2]. Brain injury in the preterm infant is associated with multiple risk factors, including lower gestational age (GA) at birth, fetal growth restriction, days of mechanical ventilation, the duration of parenteral nutrition, necrotizing enterocolitis, and male sex [3]. This review presents current evidence regarding the clinical factors associated with brain injury in preterm infants with necrotizing enterocolitis needing surgical intervention. We present information from clinical and laboratory research in conjunction with information collected from an extensive search in PubMed, EMBASE, and Scopus databases.

NEC and White Matter Injury (WMI):

Preterm infants with NEC, especially those requiring surgery, have higher inflammatory markers in the blood, severe white matter abnormalities on brain imaging, and adverse neurodevelopmental outcomes at two years of age [4–8]. Animal studies report systemic inflammation secondary to NEC leading to neuronal injury via microglial activation, inflammatory pathway activation, and brain barrier disruption [9–12]. A recent study [13] of 69 infants found clinical and histopathological determinants of white matter injury on neuroimaging in infants with surgical NEC. Magnetic resonance imaging (MRI) revealed brain injury in this preterm cohort with surgical NEC involving white matter in 52% of infants, grey matter in 10%, and the cerebellum in 30% [13]. Numerous clinical factors, including gestational age, RBC transfusions before NEC onset, pneumoperitoneum, age at NEC onset, postoperative ileus, acute kidney injury (AKI, defined by serum creatinine), postnatal steroids, and length of hospital stay, were correlated with WMI on univariate analysis. Compared to infants with grade 1–2 WMI, infants with grade 3–4 WMI had significantly less intestinal necrosis (1.1 ±0.9 vs. 2.0 ±1.4; p= 0.018) and higher mean intestinal hemorrhagic scores on intestinal pathology (3.1 ±1.2 vs. 2.0 ±1.0; p= 0.003) in the study cohort. Associations of RBC transfusion (OR 23.6 [95%CI: 4.73–117.97]; p=0.0001), age at NEC onset (OR 0.30 [95%CI: 0.11–0.84]; p=0.021), necrosis (OR 0.10 [95%CI: 0.01–0.90]; p=0.040) and bowel hemorrhage (OR 7.79 [95%CI: 2.19–27.72]; p=0.002) persisted in multivariable analysis with grade 3–4 WMI. The infants with WMI also displayed lower mean motor, cognitive, and language scores and higher ophthalmologic morbidity at two years of age.

In a matched-cohort analysis of 2241 infants followed-up at the age of 6 years, the authors reported that infants with surgical NEC had lower mean IQ results than unaffected controls (±SD) (85±17 vs. 94±14, p = 0.023) while no differences were found for history of SIP [14]. Roze et al. also reported that at school age (9 years), the motor functions and intelligence of many children with NEC or SIP were borderline or abnormal, and, specifically, attention and visual perception were impaired [15]. A prospective longitudinal study of extremely low gestational age newborns with NEC or SIP evaluated ND outcomes at 10 and 15 years of age and found no significant difference in neurodevelopmental outcomes from children without NEC/SIP [16]. The authors suggest early intervention services, family support, and schools could affect this, along with ‘catch-up’ growth. Sample attrition, which results in possible selection bias, could also affect these results [16]. A study by Han et al. reported that infants with severe NEC who survived did not have severe neurodevelopmental disability and participated in school (69%) at 7–16 years of age [17]. A recent meta-analysis provides evidence suggesting an association between NEC and NDI and the severity of intestinal lesions, which appears to correlate with a higher risk of NDI at 1 year of age [18].

Surgical NEC and Cerebellar Injury:

The cerebellum is vulnerable to hemorrhage, inflammatory injury, and dysmaturation in preterm infants [19] [20]. Delivery as a preterm infant may alter global, regional, and local development of the cerebellum and brainstem, even in the absence of structural brain injury on conventional MRI [21]. A recent meta-analysis [22] of 15 studies examined the primary data on maternal, obstetric, and perinatal characteristics and outcomes of infants with and without cerebellar hemorrhage. The authors reported NEC as a risk factor (OR 3.2, 95% CI (1.7–5.8), P=0.000, I2=0%) for cerebellar hemorrhage in 6 studies and subsequent neurodevelopmental consequences. Our recent retrospective study [23] compared clinical/pathological information between surgical NEC infants with and without cerebellar injury detected on brain MRI obtained at term equivalent age. Cerebellar injury patterns identified on MRI brain were cerebellar hemorrhage (CBH), siderosis, and/or cerebellar volume loss graded as: grade 1 unilateral small (≤ 3 mm) punctate lesions; grade 2 bilateral small punctate lesions; grade 3 extensive (>3 mm) unilateral lesions; and grade 4 extensive bilateral lesions [24]. Cerebellar volume loss was classified as mild (<25% volume loss), moderate (25–75% volume loss), and severe (>75% volume loss). We reported that [23] cerebellar injury (21/65, 32.3%) in preterm infants with NEC was associated with patent ductus arteriosus (PDA) (18/21(85.7%) vs. 25/44(56.8%); p=0.021), blood culture positive sepsis (13/21 (61.9%) vs. 11/44 (25%); p=0.004) following NEC (predominantly grew Gram-positive bacteria (9/21(42.9%) vs.4/44(9.1%);p=0.001)), higher red cell transfusions, higher rates of cholestasis following NEC and differences in intestinal histopathology (more hemorrhagic and reparative lesions) on univariate analysis. Those with cerebellar injury were associated with severe WMI (grade 3–4) (14/21 (66.7%) vs. 4/44(9.1%) p=0.0005) and any ROP (70.6% vs. 38.5%; p=0.027) than those without cerebellar injury [23]. On multi-logistic regression, the positive blood culture sepsis (OR 3.9, CI 1.1–13.7, p=0.03), PDA (OR 4.5, CI 1.0–19.9, p=0.04), and higher intestinal pathological hemorrhage (grade 3–4) (OR 16.9, CI 2.1–135.5, p=0.007) were independently associated with a higher risk of cerebellar injury [23]. Neubaur et al. reported the disruption of microstructure (assessed by fractional anisotropy and apparent diffusion coefficient) of cerebellar-cerebral connections in 5 vulnerable regions (the centrum semiovale, posterior limb of the internal capsule, corpus callosum, and superior and middle cerebellar peduncles) on term equivalent brain MRI in preterm infants (n=267) aged <32 gestational weeks [24].

Impact of NEC-associated Sepsis and Brain Injury:

We recently reported a higher frequency of Gram-positive infection (42.9% vs. 9.1%) in infants with cerebellar injury [23]. However, the Gram-negative positive sepsis (14.3 vs. 11.4%) was not significantly different in infants with and without cerebellar injury. In a recent meta-analysis, S. epidermidis sepsis was associated with higher odds of neurodevelopmental impairment (OR 1.31, 95% CI: 1.09–1.57) compared to non-infected infants [25]. Neonatal host responses to S. epidermidis sepsis are not fully understood. In the preterm infant, the neonatal host response is immature with a distinctive regulatory pattern [26]. A prospective study of 192 neonates (GA <30 weeks) noted that infants with Gram-positive infections associated with NEC had more WMI on MRI than those without sepsis-associated NEC on the bivariate analysis [27]. Bacteremia-associated brain injury may be explained by the release of lipopolysaccharide or peptidoglycan, which modulated proinflammatory genes in the brain such as Toll-like receptors, nuclear factor-kappa B, antioxidants, oxidants, and cytokines [28]. Preterm infants with cerebellar injury have higher mean white blood cell count (31.4± SD 22.9 vs. 20.9 ± SD 14.9; p=0.080) at day 4 following NEC, higher absolute neutrophil counts at day 4 (21.5 ± SD 18.6 vs. 11.4± SD 9.2; p=0.023) and higher monocyte counts day 7 following NEC (14.9 ± SD 6.9 vs. 21 ± SD 8.9; p=0.022) than those without cerebellar injury on brain MRI at term equivalent age [23].

Schlapbach et al. reported the impact of sepsis on neurodevelopment at 2 years corrected age in extremely preterm infants (24(0/7) to 27(6/7) weeks’ gestational age) in a Swiss national cohort [29]. Gram-positive sepsis was associated with a four-fold risk of cerebral palsy and an approximately two-fold risk of NDI. This effect was attributed mainly to coagulase-negative staphylococci sepsis (n = 77), significantly increasing cerebral palsy risk [29]. Sepsis caused by Gram-positive organisms other than coagulase-negative staphylococci (n = 43) was associated with a twofold-increased risk of NDI. Infants with Gram-negative sepsis (n = 29) had an increased risk of NDI in the univariate analysis compared with uninfected infants, but this trend was weakened after adjustment for confounders [29]. It is important to note, however, that the follow-up group was biased insofar as mortality was highest for children with Gram-negative sepsis (OR for death: 1.83 [95% CI: 1.10–3.07]) [29].

Dean et al. reported that microglia activation in the cerebellum was observed in preterm sheep, in which intravenous injection of a low dose of Escherichia coli lipopolysaccharide (LPS) led to an increased number of microglia, cerebellar white matter injury, and loss of oligodendrocytes [30]. Such preclinical studies lend credence to the idea that they provide mechanistic insights into WMI resulting from common NEC pathogens.

Blood Transfusions and Brain Injury:

Infants with NEC are frequently treated with blood product transfusions for anemia. Clinical and animal model studies have shown that anemia alters the intestinal inflammatory milieu and that subsequent RBC transfusions activate newly recruited leukocytes in the intestinal wall, possibly precipitating NEC [31–34]. The Preterm Erythropoietin (EPO) Neuroprotection (PENUT) Trial reported on the impact of red cell transfusion on subsequent neurodevelopment. Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI [1.34, 0.57]), a decrease in mean motor score of 1.51 [−1.91, −1.12], and a decrease in mean language score of 1.10 [−1.54, −0.66][35]. The exact mechanism of brain injury remains unclear, though possible mechanisms include proinflammatory injury, suppression of endogenous EPO, and oxidative stress-mediated injury to the pre-oligodendroglia following the transfusion [36]. It is also plausible that blood transfusions may be a marker for cerebral hypoxic-ischemic risk.

Sedative/Analgesic Exposure and Brain Injury:

Preterm infants with surgical NEC are commonly exposed to several sedatives, pain, and paralytic medications for the control of pain and agitation during the initial surgical treatment, during follow-up surgical procedures (re-anastomosis of bowel or for stricture/fistula repair), and recovery. Recent studies demonstrate that higher cumulative fentanyl doses in preterm infants correlate with a higher incidence of cerebellar injury and lower cerebellar diameter at term equivalent age [37, 38]. Other studies have suggested adverse neurological effects in preterm infants exposed to opioids and benzodiazepines [39]. These neuro-sedatives are hypothesized to contribute to adverse neurological outcomes via mechanisms including injury related to hypoperfusion, direct impacts on brain growth and development, as well as antiproliferative and apoptotic effects on immature neuronal cell populations [38–40]. Midazolam exposure is associated with macro- and microstructural alterations in hippocampal development and adverse neurodevelopmental outcomes consistent with hippocampal dysmaturation [39].

Our recent study [41] compared analgesic-sedative agent (ASA) use before, during, and after surgical NEC in neonates with and without WMI. Infants with any WMI (grade 2–4, n=36/67, 53.7%) had a higher number of surgical procedures managed with ASA (5 [IQR: 3, 8] vs. 3 [2, 4]; p=0.002) and had a longer duration of hypotension during their first (48.0 hours [26.0, 48.0] vs. 15.5 [6, 48]; p=0.009) and second surgeries(20 hours [0, 48h] vs. 0 [0, 22]; p=0.017). The group also received more hydrocortisone (35% vs.13.3%, p=0.04) than those without any WMI. No differences in fentanyl/morphine/midazolam exposure before, during, or after NEC onset were identified between the two groups. Additionally, infants with severe WMI (19/67, 28.3%, grade 3/4) had a higher incidence of AKI (p=0.004), more significant surgical morbidity (p=0.047), more surgical procedures (6.5 [3, 10] vs 4 [2, 5]; p=0.012), and higher mean fentanyl doses from birth until NEC onset (p=0.03) than those without severe WMI. The surgical morbidity was classified as strictures, fistulas, wound dehiscence, surgical site infections (including abscesses), adhesions, and perforations. Univariate associations between these factors and severe WMI lost significance after multivariable logistic regression. A large multicenter prospective study is needed to understand the full impact of ASA on neurodevelopmental outcomes. Given that accurate and clinically relevant assessment of cerebrovascular autoregulation remains limited [42], future studies should focus on optimizing strategies to maintain appropriate cerebral perfusion while limiting direct neurotoxicity and maximizing neuroprotection.

AKI following NEC and Brain Injury

Sarkar et al. reported that AKI was independently associated with hypoxic-ischemic lesions on brain MRI in a group of 88 asphyxiated neonates [43]. They found MRI abnormalities in 73% (25/34) of the AKI infants compared with 46% (25/54) in the no-AKI infants. In infants with surgical NEC, we noted AKI in 52.5% (n=32/61) using creatinine criteria and 42.6% (n=26/61) of cases using urine output criteria [44]. The Modified Neonatal Staging Criteria described in Improving Global Outcomes (KDIGO) Clinical Practice Guideline was used to determine AKI [45]. Infants with WMI had predominantly stage 1 AKI by creatinine criteria and stage two AKI by urine out method. Severe AKI was defined as infants with stage 2 and 3 AKI by serum creatinine and urine output criteria in the study cohort [44]. Those infants with severe AKI had more cases of white matter abnormality (90% vs. 36.6%; p<0.001) and retinopathy of prematurity (63.9% vs. 35.3%; p=0.017) than those without severe AKI (creatinine criteria). Furthermore, the infants with severe AKI (creatinine criteria) had more grade 2 loss of periventricular volume (65% vs. 30%; p<0.001), grade 2 ventricular dilatation (65% vs. 25%; p=0.001), grade 2 thinning of corpus callosum (65% vs. 27.5%; p=0.004) compared to neonates without AKI [44]. In addition, 11.7% of infants had grey matter abnormalities. These infants mainly showed loss of subarachnoid space grade 1, grey matter signal abnormality grade 1, and grade 1 gyral maturation changes. In addition, the presence of AKI stage 2–3 by serum creatinine was independently associated with higher odds of sustaining severe WMI level on an ordinal scale (OR=6.2; 95% CI= (1.1–35.5); p=0.041) [44].

The presence of AKI with surgical NEC suggests that hypovolemia may be one of the pathophysiological mechanisms that adversely influence brain perfusion and increase the risk of ischemic injury. Animal models show that AKI appears not to be an isolated event but reflects remote multi-organ dysfunction involving the heart, lungs, liver, intestines, and brain through an inflammatory mechanism involving neutrophil migration, cytokine expression, and increased oxidative stress [46].

NEC-associated Brain Injury and Pathophysiology:

Animal studies report systemic inflammation secondary to NEC leads to neuronal injury via microglial activation, inflammatory pathway activation, and blood-brain barrier disruption [9–12]. A multicenter clinical study demonstrated that Infants who developed NEC did not start with elevated blood levels of inflammatory cytokines, but these rose after the onset of NEC. NEC diagnosis was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand-2, macrophage inflammatory protein-1β/CC-motif ligand-3, and C-reactive protein [8]. Additional animal models have shown that systemic inflammation and infection sensitize the neonatal brain to neuronal injury via various proinflammatory pathways [9]. In piglets with NEC, systemic inflammation led to blood-brain barrier disruption, resulting in region-specific (hippocampus) neuronal degeneration [10]. Recently published mouse studies have denoted that activating the intestine’s inflammatory pathway activates brain microglia, leading to neuronal injury [11, 12]. Infants with WMI also develop lower lymphocyte percentages on day two after NEC onset [47]. A recent study by Zhou et al. found that the brains of mice and humans with NEC contained CD4+ T lymphocytes, which are required for brain injury development [48]. The authors demonstrated that microglial activation of gut-derived IFN-γ-releasing CD4+ T cells may mediate neuroinflammation in infants with NEC by leading to a loss of oligodendrocyte progenitor cells and myelin. Oligodendrocyte progenitor cells are the most proliferative cells in the CNS and constitute approximately 10% of cells in the human brain. Their primary function is to produce myelin-generating mature oligodendrocytes [49]. Low percentages of lymphocytes at day two may reflect the sequestration of lymphocytes in the intestine and brain tissue.

Cha et al. identified altered white matter microstructure in preterm infants with NEC, demonstrating increased mean diffusivity in the splenium of the corpus callosum (p=0.001) and the left corticospinal tract (p=0.001) [50]. Jiang et al. reported that neonatal NEC adversely affects myelination of the more rostral or central regions of the immature brainstem, as evidenced by the maximum length sequence brainstem auditory evoked response components, resulting in delayed or impaired neural conduction but spares the more peripheral regions [51].

Placental Lesions, NEC, and Brain Injury:

The risk factors associated with NEC are complex and multifactorial, including preterm birth, adverse intrauterine environment, and poor perinatal transition [52]. Chorioamnionitis (clinical and histologic combined) complicates as many as 40–70% of preterm births with premature membrane rupture or spontaneous labor [53]. Association of placental pathology with NEC severity was highlighted in a study of 237 predominantly African – American preterm infants, [54] where those with NEC (n=107) had significantly more placental lesions (53/107(49.5%) vs. 36/130 (28.1%); p=0.003) than control cases (n= 130). Infants with NEC and WMI had a significantly higher incidence of acute histological chorioamnionitis (52 % vs. 27.8 %; p=0.04) when compared with controls. On unadjusted logistic regression, acute histologic chorioamnionitis without fetal inflammatory response was associated with higher odds of WMI (OR 2.81; 95% CI 1.05 – 7.54; p=0.039). Prospective multicenter studies, including accurate and precise clinical, maternal, and laboratory predictors (e.g., inflammatory biomarkers), will help identify the mechanisms associated with the placental pathology, the development of NEC, and the impact of in-utero-triggered inflammation on WMI.

Gut Microbiome and Brain Injury:

There are interesting parallels between the preterm infant microbiome and brain development that may also impact outcomes. Preterm birth deprives preterm infants of a critical period of normal brain development and maturation in utero, whereby fundamental processes such as cortical and grey matter volumetric growth, neurogenesis, axonal and dendritic growth, synaptogenesis, and myelination, which begin in utero as early as 20 weeks gestation, are interrupted. The processes are later pruned and modified during early postnatal development [55]. Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma [56, 57]. Within the microbiome, decreased abundance in Bacteriodota, Lachnospiraceae, and Actinobacteriota have been associated with differences in head growth in preterm infants [58].

Infants’ loss of Bacteroides and Lachnospiraceae from the microbiome has been associated with alterations in functional brain connectivity [59]. Hypothetically, losing these bacteria may lead to a relative increase in Gammaproteobacteria, predisposing infants to NEC and impacting brain development [60] [57]. The proposed mechanisms by which the microbiome specifically affects preterm infant brain development include microbial modulation of both the innate and adaptive immune system, microbiota-inducing epigenetic changes in lymphoid cells, bacterial metabolites, and the effect on the blood-brain barrier [60]. Preterm infants with surgical NEC receive intravenous antibiotics and are kept nil per oral for 2–3 weeks following laparotomy, which impacts the gut microbiome and potentiates dysbiosis [61].

Growth and Nutrition factors:

A few studies report that NEC alters neurodevelopmental outcomes, but not growth, in preterm infants at 18–24 months of corrected age [62, 63]. A study by Hintz et al. found that surgical NEC was associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months of corrected age compared with infants without NEC [64]. Ramel et al. reported that linear growth suppression in VLBW infants was negatively associated with developmental outcomes at 24 months [65]. The poor growth and neurodevelopment in preterm infants most likely represent an increase in the level of proinflammatory cytokines in infants with feed intolerance/NEC compared to controls [66]. The poor growth in critically sick patients may also be due to low levels of insulin-like growth factors -I and -II as well as insulin-like growth factor binding protein-3, accompanied by elevated levels of growth hormone (GH), a consequence of developmental peripheral GH resistance [67].

Surgical intervention type and timing to operate:

Preterm infants with surgical NEC are managed with primary Penrose drain (PD) or laparotomy, with considerable uncertainty over which procedure may be preferable despite recent randomized trials [68]. Blakely et al. also failed to find differences in mortality or neurodevelopmental outcomes between the two groups [69]. In our study of a surgical cohort of 110 infants, 33% of infants received PD, and 64% received laparotomy and found no difference in mortality, WMI, and the days of total parenteral nutrition [70, 71]. A systematic review [72] by Duric et al. found that only two studies reported the timing of surgery out of 1121 screened articles. The two studies did not find any significant impact on mortality, parenteral nutritional dependence at 28 days, and the WMI [72].

The clinical factors for NEC-associated brain injury are summarized in Table 1.

Table 1:

Factors associated with NEC associated brain injury (Gut -brain axis)

Acute histological Chorioamnionitis
Age of NEC onset
Red blood cell transfusions
Less Necrosis and higher-grade hemorrhage on intestinal pathology
Gut dysbiosis
NEC associated sepsis (Gram positive sepsis)
Number of surgical procedures during NICU stay
NEC associated AKI
Hypotension following NEC and during surgery
Poor growth following NEC
Factors associated with Cerebellar injury
Patent ductus arteriosus
Gram positive sepsis following NEC
Higher grade hemorrhage on intestinal pathology
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NEC-associated ROP and Neurodevelopmental Outcomes:

A recent report of infants with surgical NEC reported that more than half developed ROP and one-third of infants had severe ROP, of which type 1 ROP was more common [73]. Infants who develop severe ROP following surgical NEC are likely to be younger, smaller, have been exposed to more O2, develop AKI, and grow poorly compared to those who do not develop severe ROP [73]. Necrotizing enterocolitis is associated with necrosis, inflammation, hemorrhage, and reparative changes on intestinal histopathological examination [74]. The hemorrhagic necrosis seen in infants with NEC is likely due to abnormal vasculature and neo angiogenesis in the intestine [75, 76]. Retinopathy of prematurity is similarly associated with abnormal vascularization development secondary to alterations in the expression of insulin-like growth factor 1 and vascular endothelial growth factor [77]. In the gut, both cytokines appear to be “vasculo-protective,” rendering consideration that NEC may result from the downregulation of these factors at the local level [78] [79].

Future Directions:

In the future, prospective multicenter studies, which allow the inclusion of additional clinical details (e.g., gut perfusion, gut microbiome) and laboratory predictors such as inflammatory biomarkers, may support earlier recognition of risk factors and pathways that lead to cerebellar and white matter injury following surgical NEC. Studies that evaluate neuroprotective strategies to prevent brain injury are greatly needed to improve neurodevelopmental outcomes in high-risk preterm infants with NEC. The neuroprotective strategies such as optimizing growth following NEC, lactoferrin, fecal microbiota transplantation, stem cell therapy, inhibition of reactive oxygen species activation, and anti-inflammatory therapies targeting the TLR4 pathway should be explored by the researchers further to have better clinical outcomes. Understanding gut - brain axis opens new opportunities for developing novel gut microbiome-modulating-based therapeutic interventions in preterm infants to mitigate neurodevelopmental impairment [55].

Acknowledgment:

The Mississippi Center for Clinical and Translational Research and the Department of Pediatrics at Wake Forest School of Medicine for supporting the NEC research.

Funding:

Parvesh Garg is partially supported by the NIH NIGMS under Award Number U54GM115428. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Footnotes

Conflicts of interest: The authors disclose no conflicts.

Consent: Patient consent is not required as per IRB

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