The presence of intestinal metabolites called bile acids in the airways of 1-year-old children genetically diagnosed with cystic fibrosis (CF) is significantly associated with early disease mechanisms and worse clinical outcomes, according to a study in Australia.
These include increased levels of airway inflammation biomarkers, greater structural lung damage, distinct lung microbial profiles, more disease exacerbation episodes, and more and longer antibiotic treatments.
“Collectively, our data implies that [bile acids] either contribute to or predict early [disease mechanisms] involved in establishing both the microbial and inflammatory landscapes in CF lungs early in life,” the researchers wrote in “Detection of bile acids in bronchoalveolar lavage fluid defines the inflammatory and microbial landscape of the lower airways in infants with cystic fibrosis,” which was published in Microbiome.
CF is a genetic condition that features the production of abnormally thick and sticky mucus, which accumulates in several organs, including the lungs, liver, pancreas, and intestines, leading to lung and digestive problems, symptoms that are common with CF.
Mucus buildup in the airways blocks airflow, causes lung inflammation, and is associated with recurrent airway infections. However, “how these processes are initiated and perpetuated in CF remains largely unknown,” the researchers wrote.
Previous studies of samples of bronchoalveolar lavage fluid (BALF) — obtained from rinsing the lungs with a saline solution — suggested bile acids, intestinal metabolites closely linked to the activity of gut microbes, may contribute to these early disease mechanisms.
Bile acids and CF disease progression
Specifically, bile acids in the BALF of preschool children with CF was associated with early airway inflammation and was a predictor of structural lung disease progression, leading researchers in Australia to examine whether bile acids in BALF samples were associated with differences in lung inflammatory and microbial landscapes, as well as clinical outcomes, in children with CF.
The researchers analyzed 121 BALF samples from 12-month-old children with CF enrolled in the Phase 3 COMBAT-CF clinical trial (NCT01270074).
The trial assessed the effectiveness of azithromycin against a placebo at reducing bronchiectasis, a condition marked by long-term widening of the lungs’ airways and excessive mucus accumulation that makes the lungs more vulnerable to infection.
In total, 49 (40%) of BALF samples had detectable levels of bile acids. The presence of bile acids was significantly associated with higher levels of biomarkers of airway inflammation.
These included infiltrated neutrophils, a type of immune cell for fighting infections, and IL8, a pro-inflammatory molecule that attracts neutrophils to inflammatory regions.
Moreover, elevated neutrophil elastase activity — a marker of bronchiectasis exacerbations and lung function decline — was significantly associated with bile acids in a small fraction of samples (9%).
Bile acids in BALF was also significantly associated with a higher median percentage of structural lung disease (0.97% vs. 0.51%) and more disease exacerbations during the first year of life (median of 1 vs. 0).
Patients with BALF positive for bile acids also received significantly more courses of oral or inhaled antibiotics (median of 3 vs. 1) and for longer periods (median of 13.4 vs. 8.5 days) than those without bile acids.
“Elevated markers of airway inflammation provide a plausible physiological defect linking poor clinical outcomes to the presence of BA in BALF,” wrote the researchers, who also found that BALF samples with bile acids had a higher bacterial burden and included more diverse bacterial communities. These samples included specimens typically associated with the upper respiratory tract.
Treatment with azithromycin, a motility agent that aids gastric emptying and reduces reflux events, didn’t reduce the probability of detecting bile acids in BALF samples, compared with a placebo. It also didn’t alter BALF’s bacterial load or diversity.
Conversely, preventive antibiotic treatment with penicillin reduced the probability of detecting bile acids in BALF, which was associated with elevated blood levels of biomarkers of cholestasis — the slowing or blockage of bile flow from the liver.
These findings highlight “a complex interaction connecting the gastrointestinal and respiratory systems in CF,” the researchers wrote.
Overall, environmental factors such as penicillin-based preventive treatments or the presence of bile acids were associated with distinct early microbial communities in the lungs of CF patients. Both factors were also associated with different inflammatory profiles.
“In this observational study, we provide evidence supporting that detection of [bile acids] in BALF constitutes an early predictor of both airway inflammation and clinical outcomes in CF,” wrote the researchers who also noted that because azithromycin use didn’t reduce bile acid in the airways, other strategies that modulate lung exposure to bile acids should be explored. “Furthermore, the identification of noninvasive biomarkers of [bile acid] exposure could provide useful tools to predict infants at greatest risk of progressive lung disease,” they wrote.