Plasma Metabolomics to Evaluate Progression of Necrotising Enterocolitis in Preterm Pigs.

Yan-Nan Jiang,Yong-Xin Ye,Søren Balling Engelsen,Ping-Ping Jiang,Bekzod Khakimov,Thomas Thymann,Per Torp Sangild

doi:10.3390/metabo11050283

Abstract

Necrotising enterocolitis (NEC) is a microbiome-dependent gut disease in preterm infants in early life. Antibiotic treatment is a common intervention for NEC. How NEC lesions, with or without antibiotics, affect plasma metabolome was explored in this study. Formula-fed preterm pigs were used as a model for human NEC and treated with saline, parenteral or oral antibiotics (n = 15–17) for four days after delivery. Gut tissues were collected for evaluation of NEC-like lesions and plasma for metabolomic analysis by proton nuclear magnetic resonance spectroscopy (1H-NMR). Metabolites were annotated, quantified and subjected to statistical modelling to delineate the effects of NEC and antibiotic treatment. Presence of severe NEC lesions, not antibiotic treatment, was the main drive for plasma metabolite changes. Relative to other pigs, pigs with severe NEC lesions had higher levels of alanine, histidine and myo-inositol, and lower levels of 3-hydroxybutyric acid and isobutyric acid. Across NEC lesion states (healthy, mild, severe), antibiotics directly affected only a few metabolites (tryptophan, 3-phenyllactic acid). Together and independently, NEC and antibiotic treatment affected circulating metabolites in preterm pigs. Amino acids and plasma metabolites, partly related to the gut microbiome, may be helpful to monitor progression of NEC lesions after proper validation.

Highlights

Necrotising enterocolitis (NEC) is a serious gut inflammatory disease affecting 3-10%of hospitalised preterm infants and has a high mortality and many co-morbidities [1]
After four days of antibiotic treatment, gut tissue was collected for NEC evaluation with the in-house scoring system at euthanisation, and plasma was collected for metabolomic analysis
The clinical conditions with antibiotic treatments to preterm infants during NEC were mimicked in our pig model, and a range of both NEC- and antibiotic-related metabolite changes were found, aided by statistical modelling to separate the effects of NEC and the antibiotic treatment

Summary

Introduction

Necrotising enterocolitis (NEC) is a serious gut inflammatory disease affecting 3-10%of hospitalised preterm infants and has a high mortality and many co-morbidities [1]. Modulations of bacterial colonization of the gut with pre-, pro- or antibiotics have been tested as preventive or therapeutic interventions for NEC. Concerns for increased antibiotic resistance limit the use of antibiotics for NEC prevention [9], and the most effective regimen of antibiotic treatment against NEC remains elusive. 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]

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Discussion

Conclusion