Metabolomic profiling of COPD patients compared to healthy controls identified 26 significantly dysregulated metabolic pathways (FDR <10%), highlighting L-sorbose and trimethylamine as novel markers.
Cross-Sectional (n=284)
Yes
Metabolomic profiling in COPD patients reveals systemic metabolic remodeling, including energetic imbalance and predominant anaerobic metabolism, highlighting novel biomarkers like L-sorbose and TMA.
Abstract Introduction Oxidative stress plays a central role in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD). Metabolomics, which enables the comprehensive identification of metabolites in biological samples, is an essential approach to uncover metabolic mechanisms underlying the disease. Objective To identify metabolites and metabolic pathways differentially regulated in patients with COPD compared with healthy individuals. Methods This multicenter cross-sectional study included 284 participants 46% female; median age 67 (58-74) years; BMI 25 (22-29) kg/m², of whom 260 had COPD post-BD FEV1%: 42% (33-55) and 24 were healthy controls. COPD patients had a smoking history of 48 (35-79) pack-years, CAT 16 (9-22), mMRC 2 (1-3), and Charlson index 4 (3-5). According to GOLD criteria, 5% were GOLD 1, 31% GOLD 2, 44% GOLD 3, and 20% GOLD 4; by grouping, 20% were GOLD A, 58% GOLD B, and 22% GOLD E. Serum samples were analyzed by mass spectrometry, processed in MassHunter Qualitative v.7.0, and pathways were evaluated using QIAGEN Ingenuity Pathway Analysis (FDR 10%). Results Twenty-six metabolic pathways were significantly dysregulated, and five were upregulated. The most relevant metabolites were L-sorbose, trimethylamine (TMA), and 2-acetyl-1,5,6,7-tetrahydro-6-hydroxy-7-(hydroxymethyl)-4H-azepin-4-one. Predicted upstream regulators included TNFRSF13C, GGT1, PER2, and FAAH. Increased L-sorbose, within the fructose/mannose pathway, suggests redirection of carbohydrate metabolism toward the pentose phosphate pathway (PPP) and polyol routes, enhancing NADPH generation and glutathione regeneration. Reduced TMA, derived from choline and carnitine, indicates altered fatty acid metabolism and hepatic FMO3-dependent oxidation within the choline-TMA-TMAO axis, potentially influenced by gut microbiota activity. Increased azepine derivative levels suggest disturbances in amino acid metabolism and aldehyde detoxification, involving ALDH and AKR enzymes regulated by the TP53/PARP1 axis. Conclusion Findings indicate energetic imbalance, predominant anaerobic metabolism, mitochondrial dysfunction, and reduced fatty acid oxidation. Activation of the PPP and modulation of TP53 support mechanisms sustaining NADPH and controlling oxidative stress and apoptosis. However, L-sorbose, TMA, and the azepine derivative have not been previously associated with COPD, representing novel findings possibly related to adaptive metabolic responses. These results reveal systemic metabolic remodeling and highlight potential antioxidant and bioenergetic pathways. Validation through prospective and multi-omics studies integrating metabolomics, proteomics, transcriptomics, imaging, and clinical outcomes is warranted to identify causal pathways and predictive biomarkers in COPD This abstract is funded by: None
Machado et al. (Fri,) conducted a cross-sectional in Chronic Obstructive Pulmonary Disease (COPD) (n=284). Metabolomic profiling vs. Healthy controls was evaluated on Differentially regulated metabolites and metabolic pathways. Metabolomic profiling of COPD patients compared to healthy controls identified 26 significantly dysregulated metabolic pathways (FDR <10%), highlighting L-sorbose and trimethylamine as novel markers.
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