Did you know that we inhale between 1500 to 14,000 micro-organisms per hour? (1)

Chronic lung diseases like asthma, COPD, interstitial lung disease, bronchiectasis and others, form a significant proportion of the disease burden in pulmonology. These diseases, although quite disparate are often punctuated by both acute infections and chronic colonisation. These two events are often linked to disease exacerbation as well as progression. However, what we do not know is whether this is a cause or effect of the disease process. It is interesting to note that as a common denominator, the respiratory epithelium in these diseases is not an innocent bystander. It actively interacts with the pathogens and it is now being increasingly recognised that a disordered and dysregulated host immune response fans the flames of airway inflammation which in turn escalates immune activation, setting up a vicious circle. In order to understand the complex interactions playing out in this ecosystem the best starting point would be the respiratory microbiome.

It was long assumed that the respiratory epithelium is sterile as common microbial culture systems failed to yield any positive microbiology. However, newer culture-independent molecular techniques have started giving us new insights into the rich and dynamic microbial ecosystem that exists down there! The microbiome includes both, micro-organisms (bacteria, viruses, fungi etc) and host cells as well as biotic and abiotic factors that mediate their interactions. We have microbiomes at every tissue site that we can imagine, the most widely accepted one being the gastrointestinal flora (microbiome).

For the purpose of this blog we shall limit ourselves to discussing the microbiome from a bacterial perspective alone. Let us start with the microbiome in healthy lungs.

Let’s imagine an island where the number of people living on it is determined by the immigration, elimination and reproduction rates of the members. In healthy lungs, this island’s total microbial burden and its membership is primarily dictated by the immigration and elimination numbers (Figure 1). In health these cancel each other out, thereby maintaining a stable population. The other interesting thing to note is that in health, this community membership is very diverse. The primary source of immigration into the lungs is from the oro- and naso-pharynx via microaspiration. It has been shown that even healthy people aspirate their oropharyngeal flora, conceivably more so during sleep when the reflexes are obtunded and the sphincters are relaxed. Accordingly, the resident microbiota include firmicutes and bacteroidetes.

“What are these names?” I hear you ask.

(Embarrassingly, I did not know them either until I learnt about the microbiome!)

Figure 2 shows the bacterial phyla on the leaves of the bacterial classification tree.  The ones found in healthy lungs include Firmicutes like Veillonella and Streptococcus and Bacteroidetes like Prevotella.

Although there is a lot of spatial variation in different regions of the lungs e.g. more air (ventilation) in the apices and more blood (perfusion) in the bases, curiously there is not much spatial variation in the members of the community. This tells us that the local environment does not have much of a say on the density or composition of the microbiota in health. Indeed, healthy lungs offer a nutritionally deficient environment compared with the nutrition-rich environment in the healthy gut.

In disease, two things happen: There is increased immigration from co-existent gastro-esophageal reflux and the altered local micro-environment puts pressures on the bacterial community wherein certain species are selected at the expense of others. Broadly speaking, the bacterial phyla tend to switch from Firmicutes and Bacteroidetes to Proteobateria with its famously notorious members like Pseudomonas and Haemophilus species. Interestingly, chronic lung diseases differ from each other in the bacterial communities selected whilst healthy lungs are similar across the board. What this means is that the local micro-environment, host immune response and selection pressures from treatments like exogenous steroids and immunosuppression differ between diseases. To quote Dickson et al. “All healthy lungs are alike; every unhealthy lung is unhealthy in its own way” which they have borrowed in turn from the literary genius of Tolstoy (1).

Bacterial community diversity decreases with increasing disease severity. Relative abundance of the selected species then enables colonisation and increased bacterial density.

This works both ways, where the host epithelium and immune response is dysfunctional and nurtures the selected microbiota providing them with nutrition. For example, local anoxia from increased mucus production and catecholamines generated as part of the immune response, potentiate biofilm formation and virulence in both Pseudomonas and Streptococcus species. The selected species in turn provide the right signals to the host epithelial and immune cells maintaining their dysfunctional state.

Irfan