Metabolomics of pulmonary exacerbations reveals the personalized nature of cystic fibrosis disease.
Background. Cystic fibrosis (CF) is a genetic disease that results in chronic infections of the lungs. CF patients experience intermittent pulmonary exacerbations (CFPE) that are associated with poor clinical outcomes. CFPE involves an increase in disease symptoms requiring more aggressive therapy. Methods. Longitudinal sputum samples were collected from 11 patients (n = 44 samples) to assess the effect of exacerbations on the sputum metabolome using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The data was analyzed with MS/MS molecular networking and multivariate statistics. Results. The individual patient source had a larger influence on the metabolome of sputum than the clinical state (exacerbation, treatment, post-treatment, or stable). Of the 4,369 metabolites detected, 12% were unique to CFPE samples; however, the only known metabolites significantly elevated at exacerbation across the dataset were platelet activating factor (PAF) and a related monacylglycerophosphocholine lipid. Due to the personalized nature of the sputum metabolome, a single patient was followed for 4.2 years (capturing four separate exacerbation events) as a case study for the detection of personalized biomarkers with metabolomics. PAF and related lipids were significantly elevated during CFPEs of this patient and ceramide was elevated during CFPE treatment. Correlating the abundance of bacterial 16S rRNA gene amplicons to metabolomics data from the same samples during a CFPE demonstrated that antibiotics were positively correlated to Stenotrophomonas and Pseudomonas, while ceramides and other lipids were correlated with Streptococcus, Rothia, and anaerobes. Conclusions. This study identified PAF and other inflammatory lipids as potential biomarkers of CFPE, but overall, the metabolome of CF sputum was patient specific, supporting a personalized approach to molecular detection of CFPE onset.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California , San Diego , CA , United States.
Robert A
RA
Quinn
Department of Biology, San Diego State University , San Diego , CA , United States.
Yan Wei
YW
Lim
Mass Spectrometry Data Center, National Institute of Standards and Technology , Gaithersburg , MD , United States.
Tytus D
TD
Mak
Department of Molecular Biology and Biochemistry, University of California , Irvine , CA , United States.
Katrine
K
Whiteson
Department of Biology, San Diego State University , San Diego , CA , United States.
Mike
M
Furlan
Department of Medicine, University of California , San Diego , CA , United States.
Douglas
D
Conrad
Department of Biology, San Diego State University , San Diego , CA , United States.
Forest
F
Rohwer
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California , San Diego , CA , United States.
Pieter
P
Dorrestein
Cystic fibrosis; Exacerbation; Mass spectrometry; Metabolomics; Personalized medicine