For infants with cystic fibrosis (CF), a new Dartmouth-led study uncovers a surprising challenge: their gut microbiome, the vital community of bacteria crucial for health, fails to mature as it should. This isn’t a minor delay; it’s a profound and persistent issue that could significantly impact these children’s long-term well-being from their earliest days.
Cystic fibrosis is a genetic disease affecting multiple organs, causing thick, sticky mucus to build up in the lungs and digestive system. This often leads to severe inflammation, particularly in the gut. In healthy babies, the gut microbiome is incredibly active, constantly changing as they grow – influenced by how they were born, whether they were breastfed, and when they start solid foods. By the age of three to five, this complex bacterial community typically settles into a stable, “adult-like” state. Dr. Benjamin Ross, an assistant professor of microbiology and immunology at Dartmouth’s Geisel School of Medicine, and his team aimed to understand this process in CF infants. “We didn’t really know how that process played out in infants with CF, so we set out to study how the gut microbiome of infants with the disease matured and if that maturation process was different compared to healthy kids,” explains Ross. Their findings, published in mBio, reveal that the gut microbiomes of CF infants are markedly different from healthy infants, with potential implications for their health.
How Researchers Explored the Infant Gut
To unravel the mysteries of the infant gut, the researchers meticulously collected and analyzed fecal samples over time. Their primary group included 40 infants with CF from northern New England, providing 190 samples collected regularly from birth up to 45 months of age. Each infant contributed several samples, allowing for a detailed look at their individual gut development.
For comparison, the team drew on a vast amount of previously published data from healthy, non-CF infants – nearly 4,000 samples from North America and northern Europe. This extensive comparison allowed for strong insights into how the gut microbiome typically develops in healthy babies versus those with CF.
The researchers used a powerful technique called shotgun metagenomic sequencing on the fecal samples. This method acts like a complete inventory, identifying all the genetic material from the bacteria in the gut. This allowed scientists to pinpoint specific bacterial species and even their unique strains, and to understand the various jobs these bacteria perform. To interpret this vast amount of data, they used advanced computational tools.
A crucial part of their approach involved creating “age models” using the healthy infant data. These models essentially learned to predict a baby’s age based on the types and quantities of bacteria in their gut. Applying these models to the CF samples helped determine if the CF infants’ microbiomes were developing at an expected pace or if they were “stalled” at an earlier stage. The models proved accurate across different healthy populations, reinforcing the link between age and gut microbiome development.
Key Discoveries: A Gut Stuck in Time
The study’s findings were clear and concerning: the gut microbiomes of infants with CF showed a “persistent developmental delay in maturation that is exacerbated over time up to 18 months of age and does not recover by 36 months.”
One of the most striking observations was the stark difference in the types of bacteria present. Compared to healthy infants, those with CF had significantly lower levels of beneficial bacteria like Bacteroidetes and much higher levels of Proteobacteria. These groups of bacteria play distinct and important roles in overall gut health, so these shifts matter.
The age models provided compelling evidence of this developmental halt. When applied to the CF samples, the models consistently predicted a “microbiota age” for CF infants that was much younger than the infants’ actual age, indicating their gut communities were falling behind. This delay was apparent from birth and continued to worsen up to 18 months, with no sign of improvement even by three years of age.
Additionally, the analysis revealed that CF microbiomes often failed to move beyond a “transitional” community type, effectively remaining in an immature state. While healthy infants typically progress through distinct developmental, transitional, and then stable phases, many CF infants remained stuck in the transitional phase, never fully reaching the mature, stable microbiome seen in healthy children. This pattern of delayed progression appeared to be unique to CF.
A significant finding revolved around a bacterium called Faecalibacterium prausnitzii. In healthy infants, this species becomes almost universally present by 24 months, playing a vital role in gut health and contributing to anti-inflammatory responses. However, in CF infants, F. prausnitzii remained at low levels. Not only was its presence reduced, but the variety of its different strains was also significantly lower in CF samples.
The study also highlighted other concerning features in the CF gut microbiome. There was an increased presence of bacteria typically found in the mouth, showing up in higher proportions in the gut. This pattern has been linked to a low-density gut microbiome, suggesting fewer beneficial bacteria are present. Furthermore, researchers observed an increase in fungi, particularly Saccharomyces and Candida, which have been associated with inflammatory bowel conditions.
These changes in the types of microbes also meant shifts in their functions. The metabolic capabilities of the CF gut microbiome were dramatically altered. Processes involved in fatty acid biosynthesis, common in a “pre-weaning” state in healthy infants, were elevated in CF, while processes for adult microbiome functions, like vitamin B7 (biotin) production, were reduced. This indicates that the CF gut is not just missing certain bacteria; it’s also lacking the crucial work those bacteria perform.
Paving the Way for New Treatments
While this study did not specifically examine how clinical factors like genetics or antibiotic use affected the microbiome, the stark differences observed in CF infants, even without considering these variables, are striking. The authors propose that the impaired function of the CFTR protein, a hallmark of cystic fibrosis, might be a primary cause of these microbiome changes.
The significant and ongoing delay in gut microbiome maturation in infants with cystic fibrosis presents a major challenge. However, this insight also opens new avenues for potential treatments. “We hope this work can include testing and developing interventions, such as probiotics or dietary changes, that may help mitigate the effect of the disease on the microbiome or supplement it with aspects that will help rescue microbiome deficiencies,” says Ross. The future holds promise for interventions that could help children with CF not just manage their symptoms, but also build a healthier foundation for life by nurturing the vital community within their gut.
Paper Summary
Methodology
This study analyzed 190 fecal samples from 40 infants with cystic fibrosis (CF) and compared them to 3863 samples from healthy infants. Researchers used shotgun metagenomic sequencing to identify gut bacteria and their functions. They developed “age models” to predict an infant’s age based on their gut microbiome, then applied these models to CF samples to assess developmental delays. Probabilistic modeling also helped categorize microbiome community types.
Results
The study found that CF infants’ gut microbiomes showed a “persistent developmental delay in maturation” which worsened up to 18 months and did not recover by 36 months. CF infants had lower levels of beneficial bacteria like Bacteroidetes and higher levels of Proteobacteria. Their microbiomes consistently appeared “younger” than their actual age and often remained in an immature “transitional” state. Key beneficial bacteria like Faecalibacterium prausnitzii were reduced in CF infants. The CF gut also showed an increase in oral-derived bacteria and fungi (Saccharomyces, Candida), and altered metabolic functions.
Limitations
The study did not include clinical factors such as CFTR genotype, pancreatic insufficiency, or antibiotic use in its primary analysis, meaning their specific impact on microbiome alterations was not fully assessed. Further mechanistic studies are suggested.
Funding and Disclosures
The authors declared no competing interests. Funding was provided by the Cystic Fibrosis Foundation and the National Institutes of Health.
Paper Publication Info
The study, titled “Persistent delay in maturation of the developing gut microbiota in infants with cystic fibrosis,” was published in the journal mBio. The authors include Paige Salerno, Adrian Verster, Rebecca Valls, Kaitlyn Barrack, Courtney Price, Juliette Madan, George A. O’Toole, and Benjamin D. Ross. The metagenomic samples are publicly available through NCBI’s Sequence Read Archive (BioProject accession number PRJNA955235)