Metabolomic Endotype of Asthma

Abstract

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.

Figure 1. Biochemicals reflecting the impact of increased NO production in Asthma

Taurine (A), lathesterol (B) and taurocholate (C) levels were increased in asthmatics (N=20) as compared with healthy controls (N=10). Data are box plots with median value and min and maximal distribution. (D) An abbreviated of the bile acid production pathway Bold are the metabolites higher in asthma. NO can cause functional impairment of the taurine transporter leading to higher taurine levels, which can be augmented by higher arichidonate levels in asthma. Nitric oxide, by increasing bile acid metabolism can result in high bile acid levels (see text for details).

Figure 2. Biochemicals indicative of augmented immune and inflammatory responses

[A] Untargeted metabolomics revealed significantly higher levels of nicotinamide, adenosine monophosphate and arachidonate were (N=20) in asthmatics as compared with healthy control subjects (N=10). Data are box plots with median value and min and maximal distribution. AMP= Adenosine 5′-monophosphate

Figure 3. Plasma steroids levels in relation to the severity of asthma

Steroid metabolites were significantly lower in severe asthmatics (N=10) as compared to nonsevere asthmatics (N=10). Data are box plots with median value and min and maximal distribution.