Journal Article

Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry

Summer, Ross, Namen, Andrew, Shafazand, Shirin, Muehlbauer, Michael J., Keller, Sascha, Newgard, Christopher B., Newby, L. Kristin, Roman, Jesse, Palmer, Scott M., Lobo, L. Jason, Ilkayeva, Olga, Neely, Megan L., Leonard, Thomas B., Suliman, Sally, Todd, Jamie L., Hesslinger, Christian

2024

Overview

Background The circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate with the presence of IPF, with the severity of IPF, or with the risk of clinically relevant outcomes among patients with IPF. Methods We analyzed enrollment plasma samples from 300 patients with IPF in the IPF-PRO Registry and 100 individuals without known lung disease using a set of targeted metabolomics and clinical analyte modules. Linear regression was used to compare metabolite and clinical analyte levels between patients with IPF and controls and to determine associations between metabolite levels and measures of disease severity in patients with IPF. Unadjusted and adjusted univariable Cox regression models were used to evaluate associations between circulating metabolites and the risk of mortality or disease progression among patients with IPF. Results Levels of 64 metabolites and 5 clinical analytes were significantly different between patients with IPF and controls. Among analytes with greatest differences were non-esterified fatty acids, multiple long-chain acylcarnitines, and select ceramides, levels of which were higher among patients with IPF versus controls. Levels of the branched-chain amino acids valine and leucine/isoleucine were inversely correlated with measures of disease severity. After adjusting for clinical factors known to influence outcomes, higher levels of the acylcarnitine C:16-OH/C:14-DC were associated with all-cause mortality, lower levels of the acylcarnitine C16:1-OH/C14:1DC were associated with all-cause mortality, respiratory death, and respiratory death or lung transplant, and higher levels of the sphingomyelin d43:2 were associated with the risk of respiratory death or lung transplantation. Conclusions IPF has a distinct circulating metabolic profile characterized by increased levels of non-esterified fatty acids, long-chain acylcarnitines, and ceramides, which may suggest a more catabolic environment that enhances lipid mobilization and metabolism. We identified select metabolites that were highly correlated with measures of disease severity or the risk of disease progression and that may be developed further as biomarkers. Trial registration ClinicalTrials.gov; No: NCT01915511; URL: www.clinicaltrials.gov .

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Amino acids / Analysis / Biological markers / Biomarkers / Care and treatment / Carnitine - analogs & derivatives / Ceramide / Ceramides / Chain branching / Cholesterol / Circulation / Clinical significance / Correlation / Death / Development and progression / Disease Progression / Esterification / Ethnicity / Fatty Acids / Fibrosis / Health risks / High density lipoprotein / Hispanic Americans / Humans / Idiopathic Pulmonary Fibrosis - metabolism / Interstitial lung diseases / Isoleucine / Leucine / Lipid metabolism / Lipids / Lung diseases / Lung transplantation / Lung transplants / Medical informatics / Medicine / Medicine & Public Health / Metabolism / Metabolites / Metabolome / Metabolomics / Methods / Mortality / Mortality risk / Patient outcomes / Patients / Pneumology/Respiratory System / Pulmonary fibrosis / Ratios / Registries / Regression analysis / Regression models / Review boards / Risk / Risk assessment / Sphingomyelin / Valine