CF therapy linked to shifts in gut and lung microbiome activity

Kaftrio, a CFTR modulator marketed as Trikafta (elexacaftor/tezacaftor/ivacaftor) in the U.S., was associated with improved lung function and nutritional status in a study. Researchers found only small changes in which microorganisms were present, but larger changes in their activity.

Those larger changes included more microbial activity related to butyrate, a fatty acid made when gut bacteria ferment fiber.

That is according to a study, “Functional and Compositional Shifts in Lung and Gut Microbiota after One Year of Treatment with Highly Effective CFTR Modulators in Cystic Fibrosis,” which included data from patients at a hospital in Spain. The study was published in the journal Archivos de Bronconeumología.

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How CFTR modulators affect the microbiome

CF causes thick, sticky mucus to build up in the lungs and other organs in the body, including those of the digestive tract. CFTR modulators are medications that target the mutated CFTR protein that is absent or does not work properly in CF. These treatments are known to ease lung and digestive symptoms, but their effects on the gut and lung microbiota, the set of microorganisms living naturally in the human body, are less clear.

To better understand those effects, researchers followed 35 patients, including 21 adults and 14 children or adolescents, who had clinically stable CF and were starting Kaftrio. The researchers collected samples of sputum (phlegm coughed up from the lower airways) and stool, both before treatment and after 12 months.

Over 12 months of Kaftrio treatment, average percent predicted forced expiratory volume (ppFEV1) increased from 70.3% to 81.5%. This measure estimates how much air a patient can force out of the lungs in one second compared with what is expected for someone of the same age, sex, height, and ethnicity. The increase was significant in both adults and children and in both male and female patients.

In the lungs, Pseudomonas aeruginosa, a type of bacteria that commonly causes serious infections in CF, tended to decrease, while Staphylococcus aureus bacteria tended to increase, but neither change was significant. Alpha diversity, which describes the number and variety of microorganisms within a sample, did not change significantly. Beta diversity, which compares microbial communities between samples, differed significantly in stool and sputum samples, but those differences accounted for only a small amount of the variation between samples.

“However, these findings reflect the 12-month post-treatment state and do not exclude earlier transient microbial changes after [Kaftrio] initiation,” the scientists noted.

Gut and lung microbes show functional changes

However, several bacteria normally found in the mouth, including Prevotella, Neisseria, and Fusobacterium, became more abundant in sputum. Researchers also found an increase in formaldehyde dehydrogenase, an enzyme bacteria can use to convert formaldehyde into formate. The researchers said this may reflect a change in how the microbes obtain energy.

In the intestines, bacteria such as Blautia, Bifidobacterium, and Anaerostipes became more abundant. Some of these bacteria are associated with butyrate production. Butyrate is a short-chain fatty acid made when gut bacteria ferment fiber. Microbial proteins involved in carbohydrate and fat metabolism also increased in stool.

Metaproteomics, which measures proteins produced by humans and microorganisms, showed that several human proteins associated with neutrophils — immune cells that respond to infection — decreased in sputum after treatment with Kaftrio. These included calprotectin subunits, myeloperoxidase, proteinase 3, and CEACAM8. Interleukin-1 beta, a protein that promotes inflammation, also decreased.

At the same time, some proteins involved in the extracellular matrix became more abundant. The extracellular matrix is the network of proteins and other molecules that provides structure to tissues. The increase in proteins such as PLOD1, PLOD3, and fibulin-1 in sputum may reflect structural changes in the airways — at least “in the context of chronic CF lung disease,” the researchers noted.

Overall, the findings suggest that Kaftrio treatment was associated with a less inflammatory, more stable relationship between the body and its microbes. “Our results support that CFTR modulation delivers its systemic benefits not by resetting the microbiota but by functionally reprogramming the host–microbe ecosystem toward a less harmful state,” the researchers wrote, noting that the study was relatively small.