Disruption of histidine and energy homeostasis in chronic obstructive pulmonary disease

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a systemic condition that is too complex to be assessed by lung function alone. Metabolomics has the potential to help understand the mechanistic underpinnings that contribute to COPD pathogenesis. Since blood metabolomics may be affected by sex and body mass index (BMI), the aim of this study was to determine the metabolomic variability in male smokers with and without COPD who have a narrow BMI range.

Methods: We compared the quantitative proton nuclear magnetic resonance acquired serum metabolomics of a male Chinese Han population of non-smokers without COPD, and smokers with and without COPD. We also assessed the impact of smoking status on metabolite concentrations and the associations between metabolite concentrations and inflammatory markers such as serum interleukin-6 and histamine, and blood cell differential (%). Metabolomics data were log-transformed and auto-scaled for parametric statistical analysis. Mean normalized metabolite concentration values and continuous demographic variables were compared by Student's t-test with Welch correction or ANOVA with post-hoc Tukey's test, as applicable; t-test p-values for metabolomics data were corrected for false discovery rate (FDR). A Pearson association matrix was built to evaluate the relationship between metabolite concentrations, clinical parameters and markers of inflammation.

Results: Twenty-eight metabolites were identified and quantified. Creatine, glycine, histidine, and threonine concentrations were reduced in COPD patients compared to non-COPD smokers (FDR ≤15%). Concentrations of these metabolites were inversely correlated with interleukin-6 levels. COPD patients had overall dampening of metabolite concentrations including energy-related metabolic pathways such as creatine metabolism. They also had higher histamine levels and percent basophils compared to smokers without COPD.

Conclusion: COPD is associated with alterations in the serum metabolome, including a disruption in the histidine-histamine and creatine metabolic pathways. These findings support the use of metabolomics to understand the pathogenic mechanisms involved in COPD.Trial registration www.clinicaltrials.gov, NCT03310177.

Keywords: China; chronic obstructive pulmonary disease; energy homeostasis; histidine; inflammation; metabolomics.

Figure 1

Quantitative 1H-NMR serum metabolomics differentiates patients with COPD from non-COPD smokers (NCS). (A) Mean normalized serum metabolite concentrations in NCS (n=59) and COPD (n=79) illustrated in a radar plot. Centroid and maximal dashed circle separately denote the minimal and maximal mean normalized concentration of all metabolites. Overall, the metabolome was dampened in COPD compared to NCS. (B) Box and whisker plots of normalized metabolite concentrations with FDR-corrected p-values ≤0.15. Concentrations of creatine, glycine, histidine and threonine were notably lower in COPD compared to NCS.

Figure 2

Metabolite concentrations are associated with pulmonary function, emphysema and inflammatory cytokine levels. Association heatmap between metabolomics and clinical data of subjects. Red and green squares reflect the negative and positive correlations, respectively; darker color denotes a higher correlation between metabolites and clinical index. For the statistically significant associations, the p-value is labelled in the corresponding square. Abbreviations: TNF-α, tumor necrosis factor α; IL-6, interleukin-6.

Figure 3

Histidine-histamine metabolism is disrupted in COPD. (A) Basophil (%) and (B) histamine concentrations are higher in COPD than in non-COPD smokers (NCS). Box and whisker plots (median, 25th and 75th percentiles, min and max). (C) Disruption of histidine-histamine metabolism in COPD. Elevated histamine can aggravate bronchoconstriction and shrink airway smooth muscle. Reduced histidine can cause recession of anti-oxidant and anti-inflammatory processes, both of which contribute to the pathogenesis and development of COPD or emphysema. R01167 is the KEGG identifier for the reaction catalysed by histidine decarboxylase.