Long-term Kaftrio increases gut microbiota diversity in CF

Antibiotic use may be reason for differences with healthy people

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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An illustration shows the human digestive tract.

Extended treatment with Kaftrio progressively increases the diversity of the microorganisms in the gut in people with cystic fibrosis (CF), a recent study suggests.

However, gut microbiota diversity remained significantly different from healthy people after about 1.5 years on the CFTR modulator, probably due to the use of antibiotics for respiratory infections. Overall, the treatment didn’t significantly improve gut function or ease gastrointestinal symptoms.

“Based on this, the modulation of CFTR alone may not be sufficient to rescue a microbiota signature observed across controls within [people with CF],” the researchers wrote in “Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis,” which was published in the Journal of Cystic Fibrosis.

CF is caused by mutations in the CFTR gene that lead to abnormally thick and sticky mucus being produced and accumulating in the lungs, digestive tract, and other organs. This mucus can lead to organ damage and causes most of the disease’s symptoms.

Along with respiratory complications, CF patients may see changes in gut microbiota, the vast community of bacteria, fungi, and viruses that colonize the gut and play in role in immune function, metabolism, and other processes.

Kaftrio (elexacaftor/tezacaftor/ivacaftor), which is sold as Trikata in the U.S., is a triple CFTR modulator that’s meant to increase the function of the CFTR protein and has been shown to be effective in clinical trials and real-world practice.

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 Gut microbiota diversity and CF

However, “there is [a] need to clarify whether patient improvements further translate at the site of the intestinal tract. This includes both [gastrointestinal] abnormalities and patient symptoms following CFTR modulator treatment, including the effects upon the gut microbiota, for which data remain scarce,” wrote researchers in the U.K. of the pilot study, which evaluated Kaftrio’s long-term effects on gut microbiota and clinical outcomes by characterizing the fecal microbiota of 20 people with CF, before and after Kaftrio, compared with 10 healthy people.

The patients were a mean age of 21 and were mostly male (75%). They had at least one copy of the F508del mutation, the most common CF-causing mutation, and most received treatment with antibiotics during the study (70%). Samples were provided before treatment, or baseline, and three and six months after starting Kaftrio. Seven participants provided samples after at least 17 months on Kaftrio.

Results at six months showed a decrease in gut microbiota diversity in the Kaftrio group, but that increased with extended treatment, particularly of core microbiota, that is, the microbes most commonly present in the gut. Although microbiota diversity remained higher in healthy people, differences with CF patients decreased with more time on Kaftrio.

Twenty-four types of bacteria accounted for more than half the differences between the patients and controls, including bacteria that produce short-chain fatty acids, which reduce gut inflammation. Interestingly, some of these bacteria were increased in patients.

A statistical analysis showed that having CF, using antibiotics, and age all contributed to variations in whole microbiota diversity.

Kaftrio didn’t significantly ease CF-related gut symptoms or improve gut function, as assessed by the Patient Assessment of Constipation‐Symptoms score and transit time, which is used to determine when consumed meals are first detected in the large intestine. Kaftrio did increase patients’ body mass index, a measure of body fat based on weight and height, over time.

According to the researchers, “future work should employ a combination of frequent/prolonged patient cohort studies and experimental model system approaches to gain a deeper mechanistic understanding of the effects of both the CFTR modulator therapies and pulmonary antibiotics on the temporal dynamics of gut microbiota composition [and] functioning.”