Progressive Metabolic Dysfunction and Nutritional Variability Precedes Necrotizing Enterocolitis.

Tiffany J Sinclair,Chengyin Ye,Reese H Clark,Donald Chace,Harvey J Cohen,Gary M Shaw,Karl G Sylvester,Tian Li,Dongyan Zhang,Xuefeng Bruce Ling,Yunliang Chen,David K Stevenson

doi:10.3390/nu12051275

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.

Highlights

IntroductionNecrotizing enterocolitis (NEC) is an acquired disease of premature neonates with a multifactorial pathophysiology that is likely influenced by both intrinsic biological factors (i.e., prematurity) and extrinsic variables including exposures inherent to medical care (i.e., nutrition).Recent evidence has demonstrated that fatty acid and protein metabolism differs significantly between premature and term infants [1,2,3]
Necrotizing enterocolitis (NEC) is an acquired disease of premature neonates with a multifactorial pathophysiology that is likely influenced by both intrinsic biological factors and extrinsic variables including exposures inherent to medical care.Recent evidence has demonstrated that fatty acid and protein metabolism differs significantly between premature and term infants [1,2,3]
There was no significant difference in sex or race/ethnicity between necrotizing enterocolitis (NEC) case and control infants

Summary

Introduction

Necrotizing enterocolitis (NEC) is an acquired disease of premature neonates with a multifactorial pathophysiology that is likely influenced by both intrinsic biological factors (i.e., prematurity) and extrinsic variables including exposures inherent to medical care (i.e., nutrition).Recent evidence has demonstrated that fatty acid and protein metabolism differs significantly between premature and term infants [1,2,3]. Metabolic differences associated with prematurity are further affected by feeding practices [3,4] and illness [2,5,6]. Standardized feeding guidelines have been associated with a lower risk of NEC in very low birth weight infants [7] and early nutrition has been shown to improve outcomes and decrease mortality [8]. The etiologic intersection between prematurity, nutrition, and NEC plausibly lies at the level of cellular metabolism. In combination with extrinsic stressors (i.e., altered microbiome, direct toxicity of nutritional macromolecules) metabolic vulnerability could lead to abnormal nutrient metabolism, disruptions in cellular energy balance, and oxidative stress initiating the pathophysiologic cascade that results in NEC [11,12,13]

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Discussion

Conclusion