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

Abstract

Short bowel syndrome (SBS) is a major cause of intestinal failure (IF) that may require long-term parenteral nutrition (PN) support. However, long-term PN is accompanied by severe complications such as catheter-related blood stream infection (CRBSI) and intestinal failure-associated liver disease (IFALD), and it is associated with high healthcare costs. In this study, we characterized the plasma metabolomic profile and investigated the role of metabolism in predicting long-term PN in pediatric patients with SBS. Untargeted metabolomics was performed in plasma samples from 20 SBS patients with PN support: 6 patients had IFALD and 14 patients had no liver disease. As controls, 18 subjects without liver or intestinal diseases were included for the analysis. SBS patients had distinct plasma metabolomic signatures compared to controls, and several pathways associated with amino acid metabolism and cell death were significantly changed. The presence of IFALD in SBS was associated with alterations of metabolites mainly classified as “amino acids, peptides, and analogues” and “benzene and derivatives”. Serum direct bilirubin levels were negatively correlated with levels of uridine, skatole, and glabrol. Importantly, SBS patients with long-term PN showed significantly increased levels of glutamine compared to those in the short-term PN group. Finally, using multivariate logistic regression analysis, we developed a prediction model including glutamine and creatinine to identify pediatric SBS patients who need long-term PN support. These findings underscore the potential key role of the metabolome in SBS with IF and suggest that metabolomic profiles could be used in long-term PN assessment.

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

“…In summary, this work offers a unique resource of metabolomic profile in PNALD coupled with experimental validations in animal and cellular models. Not only does our work further validate previous studies in humans, 6 but it also confirms our hypotheses in animal models. Our study establishes potentially causal mechanisms in PNALD involving phenylalanine catabolism, thereby laying the groundwork for using serum phenylalanine as a noninvasive biomarker to identify IF patients who may develop PNALD after long‐term PN.…”

“…In summary, this work offers a unique resource of metabolomic profile in PNALD coupled with experimental validations in animal and cellular models. Not only does our work further validate previous studies in humans, 6 but it also confirms our hypotheses in animal models.…”

“…We next performed the pathway enrichment analysis using the KEGG database (Figure 1C,D). Consistent with our previous findings, 6 several amino acid metabolismassociated pathways were significantly enriched in TPN groups at both time points, suggesting a critical role of dysregulated amino acid metabolism in the pathogenesis of PNALD (Figure 1C,D). Interestingly, "phenylalanine, tyrosine and tryptophan biosynthesis" and "phenylalanine metabolism" pathways were significantly enriched after 2 weeks of TPN (Figure 1D), indicating a possible link between dysregulated phenylalanine metabolism and TPN administration.…”

“…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 6 …”

“…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. 6 As our previous studies shed light on a link between amino acids and PNALD, we next performed targeted metabolomics (amino acids, fatty acids, sugars, bile acids, acylcarnitines, phenols, and indoles) in serum samples from piglets administered with total parenteral nutrition (TPN), a well-recognized animal model of PNALD, 7,8 for 1 or 2 weeks. We identified a significant increase in phenylalanine level and dysregulation of phenylalanineassociated metabolism pathways after 2 weeks of TPN.…”