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Stanford Study Reveals Cystic Fibrosis-related Shifts in Lung Microbiome

NEW YORK (GenomeWeb News) – A study by Stanford University researchers suggests the healthy human lung is home to diverse microbial communities that are somewhat distinct from those found in the lungs of individuals with cystic fibrosis.

The team started by using 16S ribosomal RNA sequencing and other methods to characterize and quantify microbial community members in sputum samples from 16 individuals with and nine individuals without cystic fibrosis. The study, appearing online today in Science Translational Medicine, indicates that bacterial communities in the lungs of cystic fibrosis sufferers differ in more than just the presence of known pathogens.

Rather, researchers report, individuals with cystic fibrosis carry characteristic microbe communities in their lungs that differ from healthy lung microbiomes at the bacterial family and phylum levels. Moreover, advancing infection and lung inflammation in the cystic fibrosis group tended to correspond with a dip in microbial diversity in the lungs, hinting that the makeup of the microbiome as a whole may be as important to lung health as the presence of specific bugs.

"The strong connection between microbial diversity and inflammation in the lung directly connects clinical parameters with quantitative details of microbial ecology," co-senior authors Carlos Milla, David Cornfield, and Stephen Quake and their co-author Paul Blainey, all based at Stanford, noted, "and suggests that the pattern of diversity contributes more to clinical presentation than the load of any particular pathogen."

While cystic fibrosis itself stems from autosomal recessive mutations affecting a gene called CFTR, which codes for the cystic fibrosis transmembrane conductance regulator, the chronic lung problems that cause most cystic fibrosis deaths often include complex bacterial infections.

In particular, researchers explained, cystic fibrosis patients sometimes benefit from antibiotic treatment even when antibiotic-resistant pathogens seem to persist in their lungs, suggesting that the presence of such pathogens may explain only part of the infection story.

To get a more complete view of the microbes that could contribute to chronic lung disease in cystic fibrosis, researchers used high-throughput 16S ribosomal DNA sequencing to compare microbial community members in sputum samples from those with or without cystic fibrosis. They also did real-time and digital PCR experiments to help quantify bacteria based on 16S amplicon levels.

The investigators identified bacteria from numerous phyla when they delved into Roche 454 Titanium 16S sequence data on sputum samples for 16 individuals with cystic fibrosis and nine unaffected controls.

But while bacteria from the phylum Firmicutes were the most common in samples from both patient and control groups, they reported, the microbial communities in sputum samples were much more diverse than those found in cystic fibrosis samples.

Healthy lung microbiomes also tended to include more previously unidentified organisms, along with a bigger dose of bugs from phyla such as Bacteroidetes and Fusobacteria. In contrast, microbiomes in the cystic fibrosis patients showed a jump in organisms from the Actinobacteria phylum.

Similar differences turned up at the family level, too. And the team's principal component analyses revealed clustering of the cystic fibrosis samples that was largely distinct from healthy samples at family and phylum levels.

"This is not to say that all [cystic fibrosis] patients harbor the same microbiome," study authors explained, "but rather, that there exists a signature in the microbial profile of [cystic fibrosis] sputum."

"[T]he signature consists of the presence or increased abundance of more than half a dozen microbial families and the absence or decreased abundance of many other microbial families compared with healthy controls," they noted.

The team saw similar differences between individuals with and without cystic fibrosis when they used Ion Torrent PGM sequencing to assess microbial communities in lung tissue samples collected during routine surgeries, suggesting the sputum samples can provide a fairly accurate picture of microbial communities within the lung.

When researchers focused in on the significance of lung microbe diversity further — looking at microbial communities in a clinical context — they found that bacterial diversity tended to decline as levels of lung inflammation markers increased. In addition, bacteria from certain families in the Actinobacteria phylum became more and more common in cystic fibrosis patients with lung disease.

Based on their findings so far, those involved in the study argued that the overall composition of the lung microbiome may be more relevant to clinical features found in individuals with cystic fibrosis than the presence or absence of individual pathogens.
And, they said, an enhanced appreciation of the healthy lung microbiome and its diversity may inform future studies of and treatments for other conditions — from chronic obstructive pulmonary disease to asthma.

"Rather than aggressively prescribing broad-spectrum antibiotics," researchers suggested, "clinicians might introduce targeted antimicrobials and probiotic therapies intended to regulate pathogen activity and enhance the efficacy of natural immune mechanisms with reduced long-term toxicity to the patient and the healthy microbiome."