J Immunol. 2015 Jul 15;195(2):643-50. doi: 10.4049/jimmunol.1500736.
Metabolomic Endotype of Asthma.
- 1Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195;
- 2Metabolon, Inc., Durham, NC 27713; and.
- 3Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
- 4Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195;
- 5Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195.
- 6Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; email@example.com.
Metabolomics, the quantification of small biochemicals in plasma and tissues, can provide insight into complex biochemical processes and enable the identification of biomarkers that may serve as therapeutic targets. We hypothesized that the plasma metabolome of asthma would reveal metabolic consequences of the specific immune and inflammatory responses unique to endotypes of asthma. The plasma metabolomic profiles of 20 asthmatic subjects and 10 healthy controls were examined using an untargeted global and focused metabolomic analysis. Individuals were classified based on clinical definitions of asthma severity or by levels of fraction of exhaled NO (FENO), a biomarker of airway inflammation. Of the 293 biochemicals identified in the plasma, 25 were significantly different among asthma and healthy controls (p < 0.05). Plasma levels of taurine, lathosterol, bile acids (taurocholate and glycodeoxycholate), nicotinamide, and adenosine-5-phosphate were significantly higher in asthmatics compared with healthy controls. Severe asthmatics had biochemical changes related to steroid and amino acid/protein metabolism. Asthmatics with high FENO, compared with those with low FENO, had higher levels of plasma branched-chain amino acids and bile acids. Asthmatics have a unique plasma metabolome that distinguishes them from healthy controls and points to activation of inflammatory and immune pathways. The severe asthmatic and high FENO asthmatic have unique endotypes that suggest changes in NO-associated taurine transport and bile acid metabolism.
Asthma has become an epidemic, affecting over 300 million people worldwide, including ~25 million people in the United States. Airway inflammation, smooth muscle bronchoconstriction leading to airflow obstruction, and mucous hypersecretion are clinical hallmarks of asthma (1). The causes of asthma remain unclear, however it is apparent that asthma is the result of a broad range of immunological, inflammatory and biochemical perturbations. Despite the recognized heterogeneity of asthma, standard evaluation and treatment is based subjective symptoms, or measures of airflow obstruction and therapy is limited to treatment of symptoms, reversing bronchoconstriction with β-adrenergic agonists and treating inflammation with corticosteroids (2). Therefore, a continued effort is being made to identify potential biomarkers using various omics technologies in order to develop evidence based therapeutic strategies (3,4). Using untargeted and targeted metabolomics strategies we find that asthma is systemic disorder wherein a number of systemic effects are related to the production of NO by the lungs and possibly other organs and tissues. As shown in the figure, nitric oxide causes an increase in extracellular taurine concentration by increasing its efflux from the intracellular compartment and by decreasing its cellular uptake by interfering with the taurine transporter. Additionally activation of the inflammatory pathway via leukotrienes further causes taurine efflux from the intracellular sites. Nitric oxide, in addition, modulates the metabolism of bile acids causing an increase in the concentration of bile acids in the plasma. Additional evidence of heightened immune response was seen as increased levels of nicotinamide in subjects with asthma. Thus the described metabolomics endotype of asthma could be used to develop biomarkers of asthma and to develop therapeutic intervention strategies aimed at treatment of whole body responses rather than symptomatic treatment of airway constriction.
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