Greater Gut Bacterial Diversity Evident With Kalydeco’s Use
Two months of treatment with Kalydeco (ivacaftor) by cystic fibrosis (CF) patients who carry a CFTR gating mutation significantly increased the diversity of bacteria in the gut but not in the respiratory system, a small study reported.
A larger and longer study might be necessary to best determine how treatment affects the respiratory system, its researchers wrote, as previous work “suggest[s] that development of respiratory tract microbiota is presaged by gut colonization patterns and nutritional factors.”
Kalydeco, by Vertex Pharmaceuticals, is approved to treat people with CF who carry gating mutations in the CFTR protein, a channel that transports chloride ions and water in and out of cells.
These mutations cause the channel to remain closed, blocking the flow of ions and water, which leads to thick mucus buildup. Kalydeco is designed to keep the channel open longer, improving lung function and sweat chloride secretion.
Studies show that the altered CFTR protein changes the composition of microbes (microbiota) in the airways and digestive system, which is associated with infection and inflammation.
Researchers in the Netherlands wondered if Kalydeco’s use, by improving ion and fluid flow and thereby mucus clearance, affected the microbiota in the airways and gut of people who carry the CFTR gating mutation S1251N.
Their study included five males and 11 females with a mean age of 22.5. Samples for each person were collected from the upper part of the throat behind the nose (nasopharyngeal), the throat at the back of the mouth (oropharyngeal), sputum, and feces one day before and two months after starting with Kalydeco.
Additional samples were also collected from eight patients, nine months and one year after treatment start. The team conducted a genetic analysis to identify the types of bacteria present in the samples.
The most abundant bacteria found in the nasopharyngeal area were Staphylococcus epidermidis, followed by Corynebacterium, Haemophilus, and Pseudomonas spp. Most abundant in oropharyngeal samples were Prevotella, Streptococcus, Veillonella, and Rothia.
Sputum samples contained Pseudomonas aeruginosa — a bacteria commonly found in CF patients — and Prevotella, Streptococcus, Veillonella, and Rothia. Abundant bacteria in feces were Enterococcus, Bifidobacteria, and Blautia.
Although not statistically significant, results showed a trend toward increasing alpha diversity in sputum samples — the bacterial diversity within a sample — but no significant changes in the overall microbial composition over time.
“Although all patients had the same mutation, baseline [pre-treatment] characteristics and baseline microbial composition differed greatly between patients, particularly in sputum samples,” the team wrote. “It would be interesting to look at differences of the effect of ivacaftor [Kalydeco] on clinical outcomes and microbial changes between patients with different baseline microbial profiles.”
Researchers saw no changes in alpha diversity or overall composition in nasopharyngeal samples. Likewise, Kalydeco treatment had little effect on oropharynx samples.
Previous studies, however, suggest that the composition of respiratory tract microbiota is affected by colonization patterns elsewhere and “multiple other factors,” the researchers wrote. “It might therefore be that longer follow-up time is necessary to ultimately be able to detect significant changes in respiratory microbiota following ivacaftor treatment.”
Notably, a significant increase over time in alpha diversity in fecal samples after the start of Kalydeco treatment was seen. In addition, the composition of bacteria in fecal samples significantly changed following treatment.
In those samples obtained a year after beginning with Kalydeco, researchers found a more diverse community composition compared to before treatment.
“In conclusion, ivacaftor enhances bacterial diversity in the gut of subjects with CF with one S1251N mutation,” the investigators wrote.
Dietary changes could be important to gut microbial composition during Kalydeco therapy, but the researchers noted their study did not assess such changes.
“In the future, the effects of diet and dietary changes in relation to microbial changes after use of CFTR modulators should be taken into account,” they added.
The team also mentioned the small sample size and the short follow-up period as additional study limitations.