2 October 2019

Lung bugs under the microscope, at last

Research Respiratory

The role of the lung microbiome has been slow to come into focus, but a growing body of evidence suggests it is a crucial player in just about every airway disease.

Professor Jodie Simpson from the School of Medicine and Public Health at Newcastle University in NSW, speaking about lung dysbiosis in severe asthma at the ERS Congress in Madrid, said studying the microbiome would ultimately allow clinicians not only to measure disease severity but also to predict exacerbations and treatment outcomes.

Very few studies had been done on asthma and the lung microbiome, she said, but they had shown that asthma patients have a far greater bacterial burden than healthy participants.

The highest bacterial loads are in those with more severe disease and in those with low or normal eosinophil counts. About half of asthma patients have low-eosinophil (aka T2-low or non-T2) asthma, which is less well characterised and treated than eosinophilic asthma.

The composition of the microbiome is also different in asthmatics.

Firmicutes and proteobacteria are far more abundant in asthma and COPD patients, especially the Haemophilus, Moraxella and Streptococcus taxa. These proteobacteria are associated with higher neutrophils, while firmicutes are higher in non-neutrophilic asthma. Streptococcus is higher in eosinophilic asthma while haemophilus is higher in neutrophilic asthma.

The composition of the microbiome also varies with BMI (bacteroides and firmicutes) and worse asthma control (proteobacteria).

However, Professor Simpson said it was still uncertain whether the bacteria were affecting the inflammatory profile or vice versa, and that microbiome-targeting treatment would be limited until that was known.

“Asthma was never thought to be associated with bacteria,” she told The Medical Republic. “But when you start looking for them you find them.

“In asthma there’s an alteration in the immune response, even in T2-low people. What we know is that the phagocytes – the macrophages and the neutrophils that are responsible for clearing bacteria and viruses out of the lungs – they don’t work as well. And my favoured hypothesis is that that’s what’s causing the problems: they’re not clearing bacteria and there’s an overgrowth of pathogens.”

Professor Simpson said that since the discovery that the lungs were not in fact sterile (“We used to think the earth was flat, too”), lung microbes had gradually been implicated in all respiratory conditions.

“The lung microbiome’s relevant in every facet of airway function in every disease – in COPD, in bronchiectasis, in cystic fibrosis, in pulmonary fibrosis – there’s a whole world of bacteria there,” she said.

“When you add changes in the immune system and inflammation, and you add medications like inhaled steroids, then you get alterations in that bacteria, and we don’t know yet what all the consequences of that are.

“We know that altering the gut microbiome has an effect on gut diseases and it’s the same in every respiratory disease. It’s just that now the technology is available for us to start looking and being able to understand what the mechanism is.

“We need to measure bacteria, we need to measure inflammation – they’re the key messages.”

Professor Simpson was involved in the AMAZES study, published in The Lancet in 2017, which found asthma patients treated with azithromycin on top of their usual medications (inhaled corticosteroids and long-acting beta agonists) had substantially fewer exacerbations and improved quality of life.

Azithromycin changed the composition of the microbiome, reducing its diversity, without lowering the bacterial load. Haemophilus influenzae was notably reduced.

While it was exciting to have a potential new treatment, Professor Simpson told the conference, the risk of microbial resistance meant antibiotics had to be used with caution.

A potentially more promising avenue for treatment was bacteriophages.

These had the advantage over antibiotics that they could be very specifically targeted, rather than killing everything in sight. Unlike antibiotics, they could evolve to keep up with bacteria’s evolution, outrunning the resistance problem. And they could alternatively be used as transporters to stimulate an immune response.

A new study presented at the conference by Dr Melanie Clerc, from the Centre for Inflammation Research at the University of Edinburgh, linked respiratory infections in babies to whether their microbiota were organised into large, well-connected clusters. Infants with more fragmented networks suffered more respiratory infections by age two.

Professor Simpson also chaired a session titled “The microbiome: novel data across respiratory diseases”, which included eight presentations including on lung microbiota and bronchiectasis, the microbiome’s role in immune response to respiratory syncytial virus, and the airway resistome (resistance genes) in chronic respiratory disease.

Gut and lung microbes are also being studied for their role in lung cancer and response to immunotherapy in the US and Australia.