Metabolites Associated With Lower Airway Infection and Inflammation

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by Lindsey Shapiro PhD |

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Levels of several metabolites were associated with inflammation and the presence of bacteria in the lower airways of people with cystic fibrosis (CF), which could be used as disease biomarkers, according to a recent study.

“Our study was the first to both examine these metabolites in lower airway samples and identify networks of relationships between metabolites and lower airway bacterial communities,” Jack O’Connor, a researcher at Lurie Children’s Hospital and the study’s lead author, said in a press release.

“We discovered metabolite biomarkers that could be related to biochemical processes associated with increased inflammation and bacterial burden in the CF lung. These features that are unique to CF lung biology could eventually aid the development of new treatments and diagnostics,” he added.

The study, “Network Analysis to Identify Multi-Omic Correlations in the Lower Airways of Children With Cystic Fibrosis,” was published in Frontiers in Cellular and Infection Microbiology

Chronic lung infections and inflammation can result in progressively worsening lung disease, the leading cause of severe disease and mortality in CF patients. However, how this happens is not well understood, particularly in the lower respiratory tract. Metabolites are intermediate or end products, such as amino acids, organic acids, sugars, or lipids, that take part in or are produced as part of cellular metabolism.

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A multi-center team led by researchers at Lurie Children’s Hospital examined metabolites and bacterial communities in the lower airways of 68 people with CF at 13 centers in the U.S., and 22 without CF, who served as controls.

Samples from the lower airways were collected with bronchoalveolar lavage fluid (BALF). In this procedure, a thin instrument called a bronchoscope is inserted into the airways, where it releases a small amount of fluid. The fluid, now containing samples of metabolites and bacteria present in the lower airways, is re-collected and examined.

The researchers performed a metabolomics analysis — a large-scale study of the metabolites present in a sample — to better understand the ongoing biochemical processes in the lungs, and genetic sequencing to identify prevalent bacteria.

CF patients had more airway inflammation and more positive BALF cultures, indicating bacterial presence, than control samples did. Specifically, two common infection-causing bacteria in CF — Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus — were increased in CF patients.

Two types of metabolites were notably altered in CF BALF. Specifically, levels of amino acids (the building blocks of proteins) were elevated and acylcarnitines, which play a key role in cellular energy production, were diminished compared to BALF from the controls.

Higher amino acid and lower acylcarnitine concentrations correlated with increased inflammation and a greater bacterial burden in the lungs, suggesting they may serve as inflammation and infection biomarkers in CF, the research team suggested.

Both amino acids and acylcarnitines have been previously associated with inflammation, further supporting this hypothesis, the researchers said.

Another metabolite, L-methionine-S-oxide, was significantly higher in CF airways and also could predict the presence of CF. Previous studies showed that L-methionine-S-oxide was associated with lung damage and airway infiltration of neutrophils — an immune cell type — in the disease’s early stages.

Metabolite levels correlated significantly with greater amounts of Staphylococcus bacteria, and with lower levels of three types of anaerobic bacteria, or those that do not require oxygen to survive, Prevotella, Streptococcus, and Veillonella. 

The findings suggest that L-methionine-S-oxide may be an important player in the cross-talk between the metabolome and lung bacteria, the researchers noted.

“It could be a defining feature of the CF airway metabolome that correlates with the CF lung’s intense inflammation and enhanced bacterial burden which sets the stage for chronic infection and lung damage and should be further investigated,” the researchers wrote.

Overall, the study’s findings suggest a complex and dynamic relationship between metabolites, the immune system, and bacteria that likely drives CF lung damage. Information gained from the study can be used to guide developing new treatments for CF lung disease, the researchers emphasized.

“Our findings are in the very early stages of research and are not yet ready for clinical applications,” said Theresa Laguna, MD, division head of pulmonary and sleep medicine at Lurie Children’s and associate professor at Northwestern University. Laguna is also the study’s senior investigator.

“Our results lay important groundwork for future studies that ultimately will advance clinical care for children with CF,” she said.