Progressive Metabolic Dysfunction and Nutritional Variability Precedes Necrotizing Enterocolitis

Abstract

Necrotizing Enterocolitis (NEC) is associated with prematurity, enteral feedings, and enteral dysbiosis. Accordingly, we hypothesized that along with nutritional variability, metabolic dysfunction would be associated with NEC onset. Methods: We queried a multicenter longitudinal database that included 995 preterm infants (<32 weeks gestation) and included 73 cases of NEC. Dried blood spot samples were obtained on day of life 1, 7, 28, and 42. Metabolite data from each time point included 72 amino acid (AA) and acylcarnitine (AC) measures. Nutrition data were averaged at each of the same time points. Odds ratios and 95% confidence intervals were calculated using samples obtained prior to NEC diagnosis and adjusted for potential confounding variables. Nutritional and metabolic data were plotted longitudinally to determine relationship to NEC onset. Results: Day 1 analyte levels of alanine, phenylalanine, free carnitine, C16, arginine, C14:1/C16, and citrulline/phenylalanine were associated with the subsequent development of NEC. Over time, differences in individual analyte levels associated with NEC onset shifted from predominantly AAs at birth to predominantly ACs by day 42. Subjects who developed NEC received significantly lower weight-adjusted total calories (p < 0.001) overall, a trend that emerged by day of life 7 (p = 0.020), and persisted until day of life 28 (p < 0.001) and 42 (p < 0.001). Conclusion: Premature infants demonstrate metabolic differences at birth. Metabolite abnormalities progress in parallel to significant differences in nutritional delivery signifying metabolic dysfunction in premature newborns prior to NEC onset. These observations provide new insights to potential contributing pathophysiology of NEC and opportunity for clinical care-based prevention.

Emerging Biomarkers for Prediction and Early Diagnosis of Necrotizing Enterocolitis in the Era of Metabolomics and Proteomics

“…Specifically, review of the literature revealed 15 clinical studies reporting on metabolomics and proteomics potential in discovering NEC biomarkers published within the last 11 years. Among them, five studies dealt with metabolomics (104,107,109,111,112), six with proteomics (82,88,(101)(102)(103)110), while four studies integrated metabolomics with either proteomics (one study) (105) or metagenolics (three studies) (87,106,109). A total of 349 infants with either suspected or definite NEC, 147 infants with sepsis/NEC, and 1,164 matched controls were included ( Table 2).…”

“…A total of 349 infants with either suspected or definite NEC, 147 infants with sepsis/NEC, and 1,164 matched controls were included ( Table 2). The most commonly used specimens for omics analysis were urine in five studies (87,103,104,111,112), stool in four studies (103,105,108,109), and plasma/serum in four studies (101,105,107,110), while surgically excised intestinal/colon tissues, dry blood spots, and buccal swabs each was used in one study, respectively (88,102,112). These studies detected several molecules that differed significantly between NEC cases and controls.…”

“…A panel of amino acids and acylcarnitines was analyzed using tandem MS. It was found that early levels and serial changes of a number of metabolites were associated with the development of NEC (112). In summary, neonates who are about to develop NEC manifest early changes in blood amino acids and acylcarnitines that progressively deteriorate until the onset of NEC.…”

“…Another limitation regarding the population included in previous omics studies is the use of different criteria for defining NEC. The most commonly used definition was based on Bell's staging II-III (82,87,102,109), or stages I-III (110,111), clinical and radiological findings (105)(106)(107)112), clinical symptoms and treatment with antibiotics (101), radiology and/or intestinal pathology findings (88), or criteria for NEC were not reported (96,100,104,109). During the last decade, the value of Bell's criteria for NEC diagnosis has been debated due to their inability to discriminate NEC from other non-NEC systemic or intestinal diseases (8).…”

Plasma Metabolomics to Evaluate Progression of Necrotising Enterocolitis in Preterm Pigs

“…Both antibiotic treatment and NEC progression can alter the composition of the gut microbiome and its metabolism [10,11], in turn affecting the host metabolism and circulating metabolites in preterm infants [12], including amino acid and lipid derivatives [13,14].…”