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A Breath of Fresh Air in Microbiome Research

Over the past few decades, the microbiome has emerged as an exciting area of research. The microbiome is a known regulator of immune homeostasis at many mucosal surfaces. However, the role of the lung microbiome in health, and how changes in it can affect disease is poorly understood. In fact, textbooks up until around 10 years ago said that the normal lung was free from any bacteria!

Discovery of the lung microbiome

It seemed unlikely that the healthy lungs were completely devoid of naturally occurring bacteria. After all, if soil samples from the most extreme regions of the earth contain colonies, surely the mucosal layer of the lungs would.

It turns out there is indeed a lung microbiome, shown by a 2010 paper that applied 16s rRNA sequencing. All bacteria contain the 16s rRNA gene, and the gene contains both conserved and variable regions. By using PCR primers for the conserved regions, and analysing the variable regions, a picture of the microbiome can subsequently be formed.

Determinants of the respiratory microbiome can be broken down into two categories. The first is microbial immigration into the lungs, and microbial elimination from the lungs. The other is a change in the regional growth conditions (pH, temperature, oxygen etc.).

Historically, patients who present with a chronic productive cough would be asked for a sputum sample. A result of “upper respiratory track flora isolated” would be treated as a negative result and ignored. Knowledge of a respiratory microbiome means that perhaps this will no longer be the case, as alterations in the airway microbiota may be important hallmarks of disease, whether causal or correlated.

Relationship of lung microbiome with disease

It has been shown that airway microbiota alterations are associated with diseases like cystic fibrosis and chronic obstructive pulmonary disease (COPD).

COPD is characterised by exacerbations or ‘flare-ups’ of symptoms, typically caused by an infection. Despite being the third leading cause of death worldwide, there have been no new treatments for over 20 years. It is known that infection is a major trigger for exacerbations, be that viral or bacterial. Viral infections have also been known to trigger secondary bacterial infections.

Aran Singanayagam, Group Leader at the Centre for Molecular Bacteriology and Infection (CMBI) at Imperial College London, is a key player in this field and has focused his studies on the effects of extrinsic therapies such as inhaled corticosteroid (ICS) on COPD exacerbations. He spoke at the Festival of Genomics and Biodata 2022 about his work.

When looking at the gut microbiome, Aran showed that COPD patients had a much larger percentage of proteobacteria than other people. Patients with frequent exacerbations had larger proportions of proteobacteria than those that didn’t and expressed lower amounts of type I and type III interferon.

A study from a different group in 2007 found that the use of Fluticasone Propionate (an inhaled corticosteroid) was associated with a much higher risk of lung infection and pneumonia. Evidence for this was shown in a mouse model where steroid treated mice produced lower antivirals when infected with rhinovirus.

Interestingly, ICS users had a disrupted respiratory microbiome when compared with non-ICS individuals, with an extremely raised population of Streptococcus.

Aran’s team hope in the future to produce models that can more robustly show a causal link between microbiome perturbations and alterations to the antiviral immune response. If this is shown to be the case, we may be able to use the gut microbiome as a therapeutic target.

Little is known about the lung microbiome, but if extrinsic therapies are having profound effects on the microbiome composition, then it could be that they need to be administered with more caution than they currently are. Hopefully, as further understanding of this niche space develops, further therapeutics will emerge, such as live microbial therapy or even antibiotics, that can balance out microbiota populations.

Image Credit: Canva

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COPD / Lung / Microbiome