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Observational Study
. 2024 Jan 25;25(1):58.
doi: 10.1186/s12931-023-02644-7.

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

Ross Summer #  1 , Jamie L Todd #  2   3 , Megan L Neely  2   3 , L Jason Lobo  4 , Andrew Namen  5 , L Kristin Newby  2   3 , Shirin Shafazand  6 , Sally Suliman  7 , Christian Hesslinger  8 , Sascha Keller  8 , Thomas B Leonard  9 , Scott M Palmer  2   3 , Olga Ilkayeva  10   11 , Michael J Muehlbauer  10 , Christopher B Newgard #  10 , Jesse Roman #  12
Affiliations
Observational Study

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

Ross Summer et al. Respir Res. .

Abstract

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 .

Keywords: Biomarkers; Interstitial lung diseases; Metabolomics; Pulmonary fibrosis.

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Conflict of interest statement

Ross Summer has nothing to report. Jamie L. Todd, Megan L. Neely, L. Kristin Newby and Scott M. Palmer are faculty members of the Duke Clinical Research Institute (DCRI), which receives funding support from Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) to coordinate the IPF-PRO/ILD-PRO Registry. Jamie L. Todd also reports grants paid to her institution from AstraZeneca and CareDx and has participated on advisory boards for Altavant Sciences, Natera, Sanofi, Theravance. Scott M. Palmer also reports research funding paid to DCRI from Bristol-Myers Squibb and Genentech and has participated on advisory boards for Altavant and Bristol-Myers Squibb. L. Jason Lobo, Andrew Namen, and Shirin Shafazand are principal investigators in the IPF-PRO Registry. Sally Suliman was previously a principal investigator in the IPF-PRO Registry. Christian Hesslinger, Sascha Keller and Thomas B. Leonard are employees of BI. Olga Ilkayeva, Michael J. Muehlbauer and Christopher B. Newgard are employees of the Duke Molecular Physiology Institute, which received funding support from BIPI for this work. Christopher B. Newgard previously served as a consultant to BI. Jesse Roman reports grants to support clinical trials as a site investigator from Bellerophon Therapeutics, BI, FibroGen, Galapagos, Hoffmann-La Roche, Horizon Therapeutics, Syneos Health; he serves as a consultant for the National Institutes of Health (NIH); he was previously a member of the Steering Committee and a principal investigator for the IPF-PRO Registry.

Figures

Fig. 1
Fig. 1
Associations between circulating metabolites and clinical analytes in patients with IPF vs. controls
Fig. 2
Fig. 2
Cumulative probability of an event of outcomes over follow-up
Fig. 3
Fig. 3
Unadjusted univariate association between circulating metabolites and risk of outcomes. Metabolites meeting statistical significance (FDR-corrected P < 0.05) or clinical significance (hazard ratio < 0.67 or > 1.5) thresholds in unadjusted or adjusted analyses are shown. *Metabolite failed proportional hazards assumptions so hazard ratios at 6, 12, and 24 months are shown. **There was a non-linear relationship between metabolite and outcome so a piecewise linear spline was used; a hazard ratio is shown for each segment
See this image and copyright information in PMC

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