The lung microbiome and the future management of respiratory disease

Up until the last decade the lungs of healthy individuals were believed to be sterile, but we now know our lungs contain a diverse species of bacteria, viruses and fungi. ^[1,2,3].  This microbial community living in our lungs (identified by its genetic material) is called the lung microbiome, and it’s not necessarily a bad thing. ^[2,4,5] Scientists are investigating the lung microbiome to see how it can provide information about an individual’s disease status, guide individual treatment decisions and improve outcomes for patients. This research also has the potential to guide the development of new respiratory medicines.

As unique as your fingerprint

The lung microbiome is analysed by taking sputum samples from individuals. Modern laboratory techniques (16S ribosomal (r) RNA and metagenomic sequencing) have enabled us to gain information about the quantity and identity of the different bacteria present in a sample. ^[4,5]

The composition of the lung microbiome is influenced by many factors and is unique to an individual.^[4,5,6] Diet, exercise, antibiotic use, ethnicity, environmental factors, ageing and life events all have an influence and cause it to change over time.^[6]

The three main factors that influence the lung microbiome are:^[1,4]

1. Different organisms moving into the airways as we breathe, from our stomachs or our mouths
2. How effectively the lungs can remove microbes
3. The conditions in the lung and how favourable they are to microbial growth

Why is the lung microbiome interesting in respiratory disease?

The importance of ‘friendly’ gut bacteria and their role in many basic functions necessary for life has been widely accepted. Over the last decade research has continued to demonstrate how the microbiomes located in different parts of our body are associated with numerous disorders including cancer, cardiovascular diseases, organ transplant rejection, Parkinson’s disease, stroke and obesity.^[2]

If we can understand the complex role of the lung microbiome in respiratory disease, we may be able to modify it in a way that improves symptoms and slows progression and perhaps, in the future this knowledge could help us find better treatments.

Lung disease results in a variety of changes in the structure of the lung tissue, altering the lung environment which in turn influences the delicate balance of the lung microbiome.^[2,6] When conditions within the lungs change certain strains of bacteria may find the new environment more favourable and start to flourish, while the ‘friendly’ strains, that prefer the healthy lungs, start to reduce in type and number. ^[2,4,6]

What about patients with asthma or COPD?

Comparison of asthmatic patients to those with no respiratory disease has shown that many asthmatic individuals have a higher proportion of potential pathogenic (harmful) bacteria, while the number of beneficial bacteria have reduced.^[5] These changes are associated with more severe disease and poorer prognosis. ^[5]

Chronic obstructive pulmonary disease (COPD) is characterised by impaired lung function and is associated with significant mortality.^[2,7] Sudden and temporary worsening of COPD symptoms are called acute exacerbations. Patients experiencing worsening of symptoms often require additional medical treatment and need hospital care. ^[2,6,8]

One of the difficulties in the management of COPD is how different the condition can be from one patient to another in terms of progression, severity, symptoms and risk of death.^[9] 

Exacerbations in any two patients with COPD may not be the same which makes it difficult for clinicians to identify patients at higher risk or those who would benefit from certain treatments.^[2,6,9] The lung microbiome is helping to understand these differences.

Evidence has shown distinct bacterial communities in the lungs of COPD patients compared to healthy subjects, and that COPD patients with a reduction in variety of bacteria have more severe disease.^[2,7,8] The lung microbiome is also helping to differentiate the types of exacerbations and factors that may lead to them. During an exacerbation, the lung microbiome alters, and studies have reported differences in the variety and quantity of bacteria present during stable disease and exacerbations.^[2,7,8]  

How are we using the lung microbiome in respiratory research?

With a 50 year history in respiratory disease research, we continue to look to the future, striving to find new ways to improve the lives of patients with respiratory conditions. Our research is investigating how changes in the different bacterial groups in the lung can inform the management of respiratory conditions and identify new targets in order to develop new treatments.

Understanding the complex interactions between the lung microbiome and our bodies will inform the way we treat respiratory disease, not just COPD, but potentially other respiratory diseases as well.

Bruce Miller, COPD Endotyping Lead, GSK Senior Fellow.

We have been joining forces with leading experts and their research teams. Using robust sampling techniques, our lung microbiome studies involve large numbers of patients and assess changes in individual patients over time.  Changes in a patient’s lung microbiome are also mapped with other clinical markers indicating inflammation or immune system activation. This provides more information on the complex interactions of the lung microbiome and respiratory health.

The factors affecting the composition of the lung microbiome are not fully understood, which is why our work is so exciting.^[5]

The future of our work could include developing vaccines or targeted drugs against specific organisms to prevent disruption to the lung microbiome, in order to reduce lung damage, reduce disease progression or even the onset of respiratory conditions.^[2]

We believe that by finding ways to modulate the lung microbiome and the immune response to specific bacteria, we will be able to identify new targets and develop innovative treatments to influence disease in a way that isn’t currently possible with existing therapies.

References

1. Dickson RP and Huffnagle GB. The lung microbiome: new principles for respiratory bacteriology in health and disease. PLOS Pathol 2015; 11(7): e1004823.
2. Domenico Maurizio Toraldoa and Luana Conte. Lung Microbiota Dysbiosis in COPD Exacerbations. J Clin Med Res 2019;11(10):667-675
3. Cookson WOCM, Cox MJ and Moffatt MF. New opportunities for managing acute and chronic lung infections. Nat Rev microbiol 2018 118(16): 111-120
4. Richardson H, Dicker AJ, Barclay H, et al. The microbiome in bronchiectasis. Eur Respir Rev 2019; 28: 190048
5. Moffatt MF and Cookson WOCM. The lung microbiome in health and disease. Clinical Medicine 2017 17(6): 525–9
6. O’Dwyer DN, Dickson RP, Moore BB. The lung microbiome, immunity and the pathogenesis of chronic lung disease. J Immunol 2016; 196(12): 4839–4847.
7. Wang Z, Bafadhel M, Haldar K, et al. Lung microbiome dynamics in chronic obstructive pulmonary disease exacerbations. Eur Respir J 2016; 47(4): 1082–1092.
8. Mayhew D, et al. Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbation 2018;73:422–430
9. Caverly LJ, Huang YJ, Sze MA. Past, present, and future research on the lung microbiome in inflammatory airway disease. CHEST 2019; 156(2): 376–382.
10. Dicker AJ, Lonergan M, Keir HR, et al. Lung Microbiome Dysbiosis is associated with Mortality in Chronic Obstructive Pulmonary Disease (COPD). ERS 2019 Abstract OA358.