A treatment that combines elexacaftor, tezacaftor and ivacaftor was associated with improvement in the gut microbiome of children with cystic fibrosis, according to a recent study by Vanderbilt University Medical Center researchers and their colleagues.
The study was published in mBio by the research team led by Maribeth R. Nicholson, M.D., M.P.H., associate professor of pediatrics, pediatric gastroenterology, hepatology and nutrition at VUMC. Co-first authors of the study were Seth A. Reasoner, an M.D./Ph.D. student involved in the research, and Rachel Bernard, D.O.
In this study, the team evaluated changes in the intestinal microbiome in a cohort of 39 children with cystic fibrosis before and after starting the three-drug combo, known as ELX/TEZ/IVA treatment.
The Gut Connection
According to Nicholson, children and adults with cystic fibrosis often have gastrointestinal comorbidities that impact quality of life and long-term health. When ELX/TEZ/IVA came onto the scene, the team wondered what might happen with patients’ GI conditions while receiving this treatment.
The triple therapy became approved in the United States for use in patients as young as two, enabling the team to examine the younger patients before and after initiating treatment with ELX/TEZ/IVA.
Nicholson emphasized that when ELX/TEZ/IVA became available, it held the promise of new era in treating cystic fibrosis, based on potential clinical impacts with the triple therapy.
To determine effects on the intestinal microbiome, the team used a technique called metagenomic sequencing to examine DNA obtained from fecal samples of patients. This enabled assessment of bacterial community composition and function before and after patients started receiving ELX/TEZ/IVA.
Impacts on the Microbiome
In this study, the team found that patients demonstrated promising changes in microbiome diversity, as well as reduced signs of intestinal inflammation and fewer antibiotic resistance genes.
Reasoner noted that Staphylococcus aureus, which frequently causes lung infections in children with cystic fibrosis, became less abundant in the gut after treatment was initiated.
“One thing we noticed was that the patients were doing clinically much better,” Reasoner said. “They were growing better and had better lung function. Their quality of life improved a lot just from being on the medicine.”
“One thing we noticed was the patients were doing clinically much better. They were growing better and had better lung function. Their quality of life improved a lot just from being on the medicine.”
Nicholson explained that at a short-term follow-up approximately six months after treatment began, the team observed a dramatic decrease in antibiotic use. Reasoner suggested that the reduction in antibiotics may have contributed to more diversity in the microbiome.
Also, he said, direct effects of the drug itself may alter the gut environment in a way that influences its microbiome. The team observed fewer microbial genes associated with acid tolerance in the stool samples, likely related to improved CFTR function in the gut and associated changes in pH.
“In the real-world experience, we see clinical improvement in our patients receiving these modulators, and we also see improvements in the composition and function of the intestinal microbiome. Collectively, these improvements will change the landscape of how we care for patients with cystic fibrosis,” Nicholson said.
Collaboration Pays Off
Nicholson said the study was conducted as a collaborative effort and faced challenges while taking place during the COVID-19 pandemic.
Researchers from a range of disciplines at Vanderbilt participated in the study, in addition to colleagues from the University of Washington in Seattle.
“One of the beauties of Vanderbilt is the capacity for investigators in different divisions and different departments to come together to answer a question,” she said.
Nicholson also said many pediatric patients seemed excited to contribute to research and voiced a desire to help other people.
Treatment with ELX/TEZ/IVA is likely to extend the lifetime for many patients with cystic fibrosis, particularly those who start on the drug as children, but gastrointestinal comorbidities must be considered. The researchers hope that deeper study of the intestinal microbiome can provide insight into these and other factors.
“The fact that we could study this in kids is important because they will hopefully go on and live longer, healthier lives. It’s a historic time to study outcomes in children with cystic fibrosis,” Reasoner said.
Nicholson has partnered with Melinda Engevik, Ph.D., of the Medical University of South Carolina, to investigate other related factors, including how changes in the intestinal mucosal layer may affect the intestinal microbiome and interact with the immune system.
“We see clinical improvement in our patients receiving these modulators, and we also see improvements in composition and function of the intestinal microbiome. Collectively, these improvements will change the landscape of how we care for patients with cystic fibrosis.”
Reasoner also hopes to investigate how certain gut bacteria may predispose patients to lung infections.
Nicholson said that ELX/TEZ/IVA has been a success story in translational research because it “moved from basic science mechanisms into a drug pretty quickly. It is an excellent example of team science.” The researchers hope the pace continues for ongoing drug discovery.
