Erlangen, Germany – Bacterial extracellular vesicles (bEVs) — tiny membrane-bound sacs released by bacteria and capable of carrying pro-inflammatory molecules — may be elevated in the bloodstream of people with cystic fibrosis (CF), particularly those with Pseudomonas aeruginosa (P. aeruginosa) lung infections.
The findings come from a pilot study published in the Journal of Cystic Fibrosis under the title “Detection of bacterial extracellular vesicles in patients with cystic fibrosis – a pilot study.” The researchers suggest that, if confirmed in larger studies, bEVs could potentially serve as biomarkers of infection, disease progression, or lung and gut barrier integrity.
P. aeruginosa and CF lung disease
People with CF produce thick mucus that can accumulate in the airways and interfere with the clearance of bacteria. This can contribute to chronic infection and persistent inflammation, which over time may damage the epithelial cells lining the lungs.
P. aeruginosa is frequently associated with serious lung infections in people with CF. Like other bacteria, it can release bEVs that bud from the bacterial membrane and may contain toxins and other components capable of stimulating inflammatory responses.
Previous research has also shown that bacterial extracellular vesicles can enter the bloodstream in other chronic inflammatory conditions, including inflammatory bowel disease. This led researchers to investigate whether a similar process occurs in CF.
Study design
The researchers analyzed blood samples from 90 participants:
- 29 people with CF and confirmed P. aeruginosa infection (PsA-positive)
- 31 people with CF without P. aeruginosa infection (PsA-negative)
- 30 healthy individuals serving as controls
The researchers isolated extracellular vesicles from the blood and examined their characteristics and bacterial-associated activity, comparing the results with clinical information.
bEVs were more abundant and generally larger in CF
Extracellular vesicles were detected in all three groups. However, vesicles from people with CF were generally larger than those found in healthy controls, with the most pronounced increase in size occurring among the PsA-negative group.
To assess bacterial vesicles specifically, the researchers examined lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria such as P. aeruginosa. LPS can provoke strong immune and inflammatory responses.
The results showed higher bEV-associated activity in people with CF than in healthy controls, with the strongest responses occurring among participants with P. aeruginosa infection.
When LPS levels were assessed relative to the number of vesicles, a significant difference was found between healthy controls and people with CF. Participants with a history of P. aeruginosa infection also tended to have more LPS associated with individual vesicles. The highest levels were seen in those with a recent infection, although this difference did not reach statistical significance and therefore could have occurred by chance.
Unexpected findings among people taking Trikafta
One unexpected observation involved people receiving Trikafta, an approved CFTR modulator. CF participants taking the treatment had significantly higher bEV-associated activity than those who were not receiving it, with the difference appearing to be driven primarily by the PsA-positive subgroup.
The finding was unexpected because Trikafta has been associated with improvements in lung function and quality of life. The researchers proposed that treatment-related changes in the microbiome or epithelial physiology could potentially alter epithelial barrier integrity and increase systemic exposure to bacterial components.
Importantly, this observation does not establish that Trikafta causes increased bEV activity or is harmful. The finding requires further investigation to understand its underlying mechanism.
Relationship with IgA
The researchers also found an association between blood levels of immunoglobulin A (IgA) and bEV-associated activity. Higher IgA levels were associated with lower bEV-associated activity.
This relationship was modest among participants receiving Trikafta and somewhat stronger among those who were not receiving the treatment. Because the study was observational, the finding demonstrates an association rather than a cause-and-effect relationship.
The main limitation: the bacterial source was not confirmed
Although the researchers detected LPS in blood samples, they were unable to definitively establish that the circulating bEVs originated from P. aeruginosa. This was identified as the study’s principal limitation.
LPS confirms the presence of components associated with Gram-negative bacteria, but it is not specific enough to identify P. aeruginosa as the source. Therefore, the findings should not yet be interpreted as proof that P. aeruginosa-derived vesicles are responsible for the increased bEV activity observed in CF.
Could the vesicles come from the gut?
The researchers also proposed that bacterial vesicles could reach the bloodstream through more than one route. While the lungs are an obvious potential source in people with CF and P. aeruginosa infection, the gastrointestinal tract may also contribute.
People with CF can experience changes in the gut microbiome, abnormal mucus, and ongoing low-grade inflammation. These factors could potentially affect the integrity of the gut barrier and allow bacterial components or vesicles to enter the circulation.
Potential role as biomarkers
The findings raise the possibility that circulating bEVs could eventually provide a blood-based measure of bacterial activity and mucosal barrier health.
If future studies can develop sensitive methods that specifically identify P. aeruginosa-derived bEVs, these vesicles could potentially be investigated as:
- biomarkers of P. aeruginosa infection;
- indicators of disease progression;
- markers of lung or gut barrier integrity; and
- measures of systemic exposure to bacterial inflammatory components.
However, these possibilities remain preliminary. The current study was a pilot investigation involving 90 participants, so it cannot establish causation or determine whether bEV measurements would improve clinical decision-making.
What comes next?
The researchers recommend larger studies to confirm the findings and develop more sensitive techniques for detecting bEVs specifically derived from P. aeruginosa. Such work could help determine whether circulating bEVs reflect infection, inflammation, or changes in lung and gut barrier integrity.
Overall, the study provides preliminary evidence that bacterial extracellular vesicles carrying inflammatory bacterial components are present at higher levels in the bloodstream of people with CF, particularly those with P. aeruginosa infection. However, the precise bacterial origin and clinical significance of these vesicles remain to be established.
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Contact
Alexander Schnell
Universitätsklinikum Erlangen