Allergy Asthma Immunol Res.  2018 Nov;10(6):628-647. 10.4168/aair.2018.10.6.628.

Obesity-Associated Metabolic Signatures Correlate to Clinical and Inflammatory Profiles of Asthma: A Pilot Study

• Liu Y
• Zheng J
• Zhang HP
• Zhang X
• Wang L
• Wood L
• Wang G

• KMID: 2441813
• DOI: http://doi.org/10.4168/aair.2018.10.6.628

Abstract

PURPOSE
Obesity is associated with metabolic dysregulation, but the underlying metabolic signatures involving clinical and inflammatory profiles of obese asthma are largely unexplored. We aimed at identifying the metabolic signatures of obese asthma.
METHODS
Eligible subjects with obese (n = 11) and lean (n = 22) asthma underwent body composition and clinical assessment, sputum induction, and blood sampling. Sputum supernatant was assessed for interleukin (IL)-1β, -4, -5, -6, -13, and tumor necrosis factor (TNF)-α, and serum was detected for leptin, adiponectin and C-reactive protein. Untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolic profiles in sputum, serum and peripheral blood monocular cells (PBMCs) were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway topology enrichment analysis. The differential metabolites were further validated by correlation analysis with body composition, and clinical and inflammatory profiles.
RESULTS
Body composition, asthma control, and the levels of IL-1β, -4, -13, leptin and adiponectin in obese asthmatics were significantly different from those in lean asthmatics. OPLS-DA analysis revealed 28 differential metabolites that distinguished obese from lean asthmatic subjects. The validation analysis identified 18 potential metabolic signatures (11 in sputum, 4 in serum and 2 in PBMCs) of obese asthmatics. Pathway topology enrichment analysis revealed that cyanoamino acid metabolism, caffeine metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, pentose phosphate pathway in sputum, and glyoxylate and dicarboxylate metabolism, glycerolipid metabolism and pentose phosphate pathway in serum are suggested to be significant pathways related to obese asthma.
CONCLUSIONS
GC-TOF-MS-based metabolomics indicates obese asthma is characterized by a metabolic profile different from lean asthma. The potential metabolic signatures indicated novel immune-metabolic mechanisms in obese asthma with providing more phenotypic and therapeutic implications, which needs further replication and validation.

Keyword

Asthma; metabolomics; endotype; obesity; obese asthma

MeSH Terms

Adiponectin
Alanine
Aspartic Acid
Asthma*
Body Composition
C-Reactive Protein
Caffeine
Chromatography, Gas
Glutamic Acid
Interleukins
Leptin
Mass Spectrometry
Metabolism
Metabolome
Metabolomics
Obesity
Pentose Phosphate Pathway
Phenylalanine
Pilot Projects*
Sputum
Tryptophan
Tumor Necrosis Factor-alpha
Tyrosine
Adiponectin
Alanine
Aspartic Acid
C-Reactive Protein
Caffeine
Glutamic Acid
Interleukins
Leptin
Phenylalanine
Tryptophan
Tumor Necrosis Factor-alpha
Tyrosine

Figure

• 

  Fig. 1 OPLS-DA of metabolic profiles on samples from obese and lean asthmatic patients. (A, D and G) Score plot of OPLS-DA model obtained from OA and LA in sputum, serum and PBMCs samples retrospectively; The labels t[1] and t[2] along the axes represent the scores (the first 2 partial least-squares components) of the model, which are sufficient to build a satisfactory classification model. (B, E, H) Permutation Test of the OPLS-DA model obtained from OA and LA in sputum, serum and PBMCs samples retrospectively; Two hundred permutations were performed, and the resulting R2 and Q2 values were plotted. Green circle: R2; blue square: Q2. The green line represents the regression line for R2 and the blue line for Q2. (C, F, I) Loading plot of OPLS-DA model obtained from OA and LA in sputum, serum and PBMCs samples retrospectively; The pq[1] and pq[2] values refer to the weight that combines the X and Y loadings (p and q). OPLS-DA, orthogonal projections to latent structures-discriminate analysis; OA, obese asthma; LA, lean asthma; PBMC, peripheral blood monocular cell.

• 

  Fig. 2 Heatmap of identified differential metabolites in sputum samples between obese and lean asthmatic patients. Red squares indicate increased expression in OA, white squares indicate no significant change, and blue squares indicate decreased expression in OA. OA, obese asthma.

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  Fig. 3 The KEGG pathway of sputum samples with red/blue dots representing the differentially expressed compounds between obese and lean asthmatic patients. Higher expression was highlighted by red dots and lower expression was labeled by blue dots. KEGG, Kyoto Encyclopedia of Genes and Genomes.

• 

  Fig. 4 The ROC curves of obese and lean asthma groups using an OPLS-DA model in sputum (A), serum (B) and PBMCs (C). ROC, receiver operating characteristic; OPLS-DA, orthogonal projections to latent structures-discriminate analysis; PBMC, peripheral blood monocular cell; TPR, true positive rate; FPR, false positive rate; AUC, area under the curve.

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  Fig. 5 MetaboAnalyst Pathway Impact based on selected and more representative metabolites responsible for the class separation in sputum samples (A) and serum samples (B), respectively. Circles represent metabolic pathways potentially involved in class separation.

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  Fig. 6 Heatmap of correlation between differential metabolites and obesity, clinical and inflammation profiles in all subjects. Blue squares indicate significant negative correlations, white squares indicate non-significant correlations, and red squares indicate significant positive correlations. PBMC, peripheral blood monocular cell; BMI, body mass index; FFM, fat free mass; PBF, percent body fat; VFA, visceral fat area; WHR, waist-to-hip ratio; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ACT, Asthma Control Test; AQLQ, Asthma Quality of Life Questionnaire; IL, interleukin; TNF, tumor necrosis factor; CRP, C-reactive protein.

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  Fig. 7 Flowchart of the screening metabolic signatures of OA. OA, obese asthma; LA, lean asthma; GC-TOF-MS, gas chromatography time-of-flight mass spectrometry; OPLS-DA, orthogonal projections to latent structures-discriminate analysis; PBMC, peripheral blood monocular cell.

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