Metabonomics reveals altered metabolites related to inflammation and energy utilization at recovery of cystic fibrosis lung exacerbation

Abstract

Background Cystic fibrosis lung disease is characterized by chronic bacterial infections in the setting of mucus abnormalities. Patients experience periodic exacerbations that manifest with increased respiratory symptoms that require intensification of therapy with enhanced airway clearance and intravenous (IV) antibiotics. Objectives In an observational study we tested if the profile of metabolites in serum distinguished the pre-from post-exacerbation state and which systemically measurable pathways were affected during the process to recovery. Methods Serum collected within 48 h of start and completion, respectively of IV antibiotics was collected from people with CF ages 6–30 years. Three day food records were collected prior to each sample. To reduce variation between subjects only subjects who had pancreatic insufficiency, had similar CF mutations, and did not have CF liver disease or diabetes were included. Metabolomic profiling was conducted by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy with metabolites being identified based on retention time/index, mass to charge ratio and comparison to known compounds. Biostatistical analyses used paired t -test with correction for multiple comparisons and orthogonal partial least square discriminant analysis. Results Thirty subjects (20 male) with a mean ± SEM age of 15.3 ± 1.2 years participated, 17 of whom had matched food-records. Lung function was significantly improved post-therapy compared to pre-therapy, (mean ± SEM) 75 ± 4% vs. 68 ± 4% predicted (n = 26). Serum metabonomics showed distinction of the pre-vs. post-therapy groups with 123 compounds contributing to the differentiation pre-versus post-antibiotics by multiple biostatistical analyses. Compounds and pathways affected included bile acids and microbial derived amino acid metabolites, increases in lipid classes of the glycerophospholipid, glycerolipids, cholesterol, phopsholipids, and most pronounced, the class of sphingolipids. Changes in n6/n3 fatty acids, decreased polyamines but increased metabolites in the nitric oxide pathway, and changes in the tryptophan-kynurenine pathway indicated decreased inflammation at resolution of exacerbation. Conclusions Changes in serum metabolites that distinguished CF pulmonary exacerbation vs. resolution of symptoms showed evidence of decreased inflammation and improvement from a catabolic state.

Bridging of host-microbiota tryptophan partitioning by the serotonin pathway in fungal pneumonia

“…Thus, 5-HT reveals a surprising protective role in lung inflammation by bridging host-microbiota interaction via Trp utilization. As a possible clinical translatability of these findings, we resorted to the Cystic fibrosis (CF) disease in which the IDO1/AhR axis and Trp metabolites have already been shown to be dysregulated 24 – 26 . We found a reduced serotonin level associated with a robust increase of its major metabolite, the 5-hydroxyindoleacetic acid (5‐OH-IAA) in mice and humans with the p.Phe508del-CFTR mutation suggesting that targeting the Trp-5-HT pathway may have clinical effects beyond the mood and behavior to encompass the coordination of host and microbial Trp metabolic pathways in lung pathologies with an inflammatory component.…”

Utilizing centralized biorepository samples for biomarkers of cystic fibrosis lung disease severity

“…Metabolomic profiling showed differences in CF and non-CF children [8] and identified lipids and metabolites that changed in response to CFTR modulator therapy [32] . Some metabolomic differences have been detected in blood at initiation of antibiotics for exacerbations compared to disease baseline [33,34] . Crosssectional comparison of serum metabolomics here showed no distinction between cohorts when correcting for multiple comparisons.…”

Kynurenine Pathway in Respiratory Diseases

“…In this study, the K/T ratio decreased after therapy, consistent with resolution of inflammation. 124 …”