Fecal sphingolipids predict parenteral nutrition–associated cholestasis in the neonatal intensive care unit

Abstract

Background: Parenteral nutrition-associated cholestasis (PNAC) in the neonatal intensive care unit (NICU) causes significant morbidity and associated healthcare costs. Laboratory detection of PNAC currently relies on elevated serum conjugated bilirubin levels in the aftermath of impaired bile flow. Here, we sought to identify fecal biomarkers, which when integrated with clinical data, would better predict risk for developing PNAC.Methods: Using untargeted metabolomics in 200 serial stool samples from 60 infants, we applied statistical and machine learning approaches to identify clinical features and metabolic biomarkers with the greatest associative potential for risk of developing PNAC. Stools were collected prospectively from infants receiving PN with soybean oil-based lipid emulsion at a level IV NICU.Results: Low birth weight, extreme prematurity, longer duration of PN, and greater number of antibiotic courses were all risk factors for PNAC (P < 0.05). We identified 78 stool biomarkers with early predictive potential (P < 0.05). From these 78 biomarkers, we further identified 12 sphingomyelin lipids with high association for the development of PNAC in precholestasis stool samples when combined with birth anthropometry. Conclusion:We demonstrate the potential for stool metabolomics to enhance early identification of PNAC risk. Earlier detection of high-risk infants would empower

Untargeted Metabolomics Reveal Parenteral Nutrition-Associated Alterations in Pediatric Patients with Short Bowel Syndrome

“…A recent study by untargeted metabolomics using stool samples from infants receiving PN showed that low birth weight, extreme prematurity, longer duration of PN, and greater number of antibiotic courses were all risk factors for developing PN-associated cholestasis (PNAC). Among all stool biomarkers for the early prediction of PNAC, 12 out of 78 were identified as sphingomyelin lipids that were positively correlated with PNAC [ 7 ]. Due to the limited number of patients with IFALD, we did not detect significant changes in the classification of sphingomyelin lipids.…”

“…Metabolomics is a comprehensive biochemical profiling technique that is used to assess systemic metabolism in a biological sample, reflecting the “net effects” of genetic, transcriptomic, proteomic, and environmental interactions [ 5 , 6 ]. The authors of a recent study performed fecal metabolomics in infants receiving PN, in which they identified 12 sphingomyelin lipids as potential biomarkers for the development of cholestasis in combination with birth anthropometry [ 7 ]. However, current studies in SBS have mostly focused on characterizing gut microbial or bile acid profiles [ 8 , 9 ], and little is known about the global metabolomic signature.…”

Targeted metabolomics unravels altered phenylalanine levels in piglets receiving total parenteral nutrition

“…A recent study performed untargeted metabolomics using fecal samples from patients with parenteral nutrition‐associated cholestasis (PNAC) identified low birth weight, extreme prematurity, longer duration of PN, and antibiotic uses as risk factors for developing PNAC. Among 78 stool biomarkers identified, 12 sphingomyelin lipids were highly associated with the development of PNAC 5 . To investigate the systemic changes in metabolomic profile associated with PNALD, we previously performed untargeted metabolomics in plasma samples from pediatric patients with short bowel syndrome (SBS) in the presence or absence of PNALD.…”

“…Among 78 stool biomarkers identified, 12 sphingomyelin lipids were highly associated with the development of PNAC. 5 To investigate the systemic changes in metabolomic profile associated with PNALD, we previously performed untargeted metabolomics in plasma samples from pediatric patients with short bowel syndrome (SBS) in the presence or absence of PNALD. Interestingly, the amino acid profile was significantly altered associated with PN, and we developed a prediction model including glutamine and creatinine to identify patients who need long-term PN support.…”

“…Metabolomics provides a systemic approach to analyze the integrated profile of biological samples to reflect the “net results” in diseases. Although several studies have characterized the metabolomic profile in feces 5 and plasma samples 6 from patients with PNALD, the underlying mechanisms remain poorly understood. A recent study performed untargeted metabolomics using fecal samples from patients with parenteral nutrition‐associated cholestasis (PNAC) identified low birth weight, extreme prematurity, longer duration of PN, and antibiotic uses as risk factors for developing PNAC.…”