High levels of bacterial sacs in blood may signal CF lung damage
Study: These vesicles could serve as indicators of disease progression
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Bacterial extracellular vesicles (bEVs) — tiny sacs released by bacteria containing pro-inflammatory molecules — have been found at elevated levels in the bloodstream of people with cystic fibrosis (CF), particularly in those whose lungs are infected with the bacterium Pseudomonas aeruginosa.
In the pilot study, the researchers call for further research to validate these findings and develop sensitive methods for detecting bEVs derived from P. aeruginosa, which could serve as diagnostic biomarkers or indicators of disease progression and lung tissue integrity.
Details of the discovery were published in the Journal of Cystic Fibrosis in the study “Detection of bacterial extracellular vesicles in patients with cystic fibrosis – a pilot study.”
P. aeruginosa frequently involved in serious lung infections in CF
The thick mucus that builds up in the lungs of people with CF impairs the clearance of bacteria, resulting in chronic infections and ongoing inflammation. Over time, this process can damage the lungs’ epithelial cells, or those that line the airways.
P. aeruginosa is a species of bacteria that’s frequently involved in serious lung infections in CF. Such bacteria can release bEVs, which bud off from the bacterial membrane and may carry toxins and other components that trigger inflammation.
In fact, bEVs have been shown to enter the bloodstream in other chronic inflammatory diseases, such as inflammatory bowel disease, a condition marked by damage to the body’s mucosal barriers.
To find out if bEVs enter the bloodstream in CF, scientists collected blood samples from 29 CF patients with a confirmed P. aeruginosa infection (PsA-positive), 31 CF patients without the infection (PsA-negative), and 30 healthy individuals who served as controls. The bEVs were isolated, and levels were correlated with clinical data.
Extracellular vesicles from CF patients were generally larger
While tests detected extracellular vesicles in the blood of all three groups, those from CF patients were generally larger than those from controls. The most pronounced increase in size was observed in the PsA-negative subgroup.
To measure extracellular vesicle levels from bacteria in particular, the team tested for the presence of lipopolysaccharide (LPS), a large molecule found in the outer membrane of bacteria such as P. aeruginosa that triggers strong immune and inflammatory responses in humans. Higher LPS-related activity, as indicated by the strong activation of an immune response in cultured cells, meant more bEVs.
Results showed that people with CF had more bEVs in their bloodstream than healthy controls, with the strongest responses observed in the PsA-positive group.
When LPS content was expressed per vesicle, a significant difference was observed between healthy controls and people with CF. Those with a history of P. aeruginosa infection had more bEV-associated LPS, with the highest levels observed in those with a recent infection, but the difference didn’t reach statistical significance, meaning it could have occurred by chance.
Unexpectedly, CF patients treated with Trikafta, an approved CFTR modulator, had significantly higher bEV-associated activity than those not receiving the therapy. This effect appeared to be driven mainly by the PsA-positive subgroup.
Our findings indicate that bEVs may play a [disease-causing] role in PsA infections in CF and be linked to barrier dysfunction in the gut and lungs.
The authors described this finding as unexpected, since Trikafta has been shown to improve lung function and quality of life. They suggested that “alterations in epithelial barrier integrity, potentially mediated by [Trikafta]-induced changes in the microbiome or epithelial physiology, may facilitate increased systemic [body-wide] exposure to bacterial components.” The microbiome is the collection of all microbes that naturally live on and in the human body.
In other tests, higher blood levels of immunoglobulin A, an antibody that plays a central role in defending mucosal surfaces, were associated with lower bEV-associated activity. This relationship was modest among Trikafta-treated patients and slightly stronger in those not receiving Trikafta.
While it was tested, a P. aeruginosa origin of the circulating bEVs could not be confirmed, which the researchers note as the main limitation of the study. Still, they detected LPS in blood samples, confirming the components of Gram-negative bacteria, the same class as P. aeruginosa.
The authors raised the possibility that bEVs could enter the bloodstream not only through the lungs but also through the gut, noting that people with CF have changes in the gut microbiome, abnormal mucus, and ongoing low-grade inflammation that could affect gut barrier function.
“Our findings indicate that bEVs may play a [disease-causing] role in PsA infections in CF and be linked to barrier dysfunction in the gut and lungs,” the researchers wrote. “Future studies should validate these results in larger cohorts and establish sensitive detection methods for PsA-derived bEVs,” which may “support the use of bEVs as diagnostic biomarkers or indicators of disease progression and barrier integrity.”
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