MSACL 2020 US Abstract

Self-Classified Topic Area(s): Metabolomics

MS-based Metabolomics Reveal Bile Acid Metabolism Dysregulation in Malnourished Children from Study of Environmental Enteropathy and Malnutrition

Xueheng Zhao(1), Rong Huang(1), Edward Dobrzykowski III(2), Khyati Mehta(1,3), Elizabeth Maier(4), Junfang Zhao(1), Sean Moore(5), S. Asad Ali(6), Carlos Prada(2), Kenneth D.R. Setchell(1,7)
(1) Division of Pathology & Laboratory Medicine, (2) Division of Human Genetics, (3) Division of Biomedical Informatics, (4)Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA (5) Department of Pediatrics, University of Virginia, Charlottesville, VA 22904, USA (6) Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan, (7) Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA

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Xueheng Zhao (Presenter)
Cincinnati Children’s Hospital

Presenter Bio: Xueheng Zhao, PhD
He is a Research Associate at the Clinical Mass Spectrometry Facility in the Division of Pathology and Laboratory Medicine at Cincinnati Children’s Hospital Medical Center. He is currently focusing on the biomarker discovery with metabolomics and lipidomics approaches to study pathogenesis of pediatric diseases. He has also been developing mass spectrometry assays for pharmacokinetic studies and clinical assays. He obtained his PhD degree from University of Georgia and MS from Stanford University.

Relevant Financial Disclosures (within past 24 months)

Grant/Research Support Bill & Melinda Gates Foundation

Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above.

Conflict mitigation NOT REQUIRED.

Abstract

Introduction
Malnutrition is the key factor associated with high mortality rate in children in the developing world. Undernutrition not only impairs physical and cognitive development but shapes long term health of these patients from an early age. The complex biomolecular perturbations induced by undernutrition at this critical window are poorly understood, especially when the malnutrition is caused by environmental enteric (EE) dysfunction or associated clinical conditions. Therefore, the challenge is to identify infants and children at risk of developmental impairment through the identification of specific biomarkers, and to then provide effective nutritional or therapeutic intervention. Mass spectrometry (MS)-based metabolomics and lipidomics are systems approaches that seek to comprehensively measure the metabolome of an individual to understand the biochemical consequences of diseases.

Objectives
The primary objective of this study was to identify specific biomarkers from the serum metabolome of malnourished children using untargeted MS-based metabolomics analysis that could then offer potential new therapies for combating malnutrition.

Methods
A cohort of 400 children from Pakistan were enrolled, of which 350 were moderate or severely malnourished and 50 were well-nourished controls. Serum samples were collected at 6 and 9 months of age before any nutritional or medical interventions. The serum metabolome was determined with ultra-performance liquid chromatography coupled to a quadrupole time-of-flight MS in extensively characterized biochemical phenotypes induced by nutritional deficiency. Identity of potential biomarkers was confirmed by both accurate mass and retention time compared with available reference standards as well as fragmentation patterns if available. Dysregulated biomarkers discovered in the untargeted analysis were confirmed and quantified by targeted analysis with UPLC-MS/MS.

Results
Untargeted MS-based metabolomics data showed reduced serum phosphatidylethanolamine and sphingomyelins in serum from malnourished children. A major biomarker discovered in the serum at 6 and 9 months of age was identified as glycocholic acid (GCA) and this bile acid was significantly elevated in the malnourished children. The increased GCA in the systemic circulation suggests reduced hepatic bile acid uptake and biliary secretion in these children. We also quantified individual serum bile acid subspecies using UPLC-MS/MS and confirmed serum GCA was significantly elevated compared with controls at 6 months (p-value 2.4e-10, fold change 2.6) and 9 months of age (p-value 4e-8, fold change 2.0). Total bile acids were also elevated at 6 (p-value 0.005) and 9 months (p-value 0.004) of age.

Conclusions
This MS-based metabolomics analysis has provided valuable insights into the biochemical changes associated with early-life malnutrition and has facilitated the discovery of candidate biomarkers as potential therapeutic targets.