POSSIBLE MECHANISMS OF GUT MICROBIOTA INFLUENCING BPD
Although the causal relationship between BPD and gut microbiota and
their exact interaction mechanisms are not sufficiently well defined, a
growing body of research suggests that gut microbiota dysbiosis can
impair the gut-lung axis, activate inflammation, and influence growth;
as shown in Figure 2 , these outcomes potentially compromise BPD
further.
Gut microbiotadysbiosis alters the
gut-lung axis
The gut microbiota may influence BPD by mediating lung immunity. A
meaningful way to accomplish this process is the gut-lung axis, which
can be articulated as a dysbiosis of the gut/lung microbiota that
affects lung/intestinal health26. Achieving this
sophisticated bidirectional crosstalk may involve both the circulatory
and lymphatic immune systems. On the one hand, intestinally produced
bacterial products (e.g., cellular debris, metabolites) reach the
pulmonary circulation via the systemic circulation, stimulating lung
immune cells (e.g., dendritic
cells (DCs), macrophages, T cells, and neutrophils) to activate
inflammation and trigger lung injury62. On the other
hand, intestinal DCs recognize the antigens and migrate towards the
mesenteric lymph nodes or gut-associated lymphoid tissue in order to
activate B and T cells, which consequently reach the lung epithelium and
activate the lung immune response62.
For example, the gut microbiota can upregulate interleukin-17A levels
which initiate granulocyte-macrophage colony-stimulating factor
signaling, which further enhances the abilities of alveolar macrophages
in relation to scavenging Streptococcus pneumoniae andKlebsiella pneumoniae 63. Neonatal mice exposed
to gut commensal bacteria had better lung mucosal defenses than those
not exposed, presumably due to intestinal DCs inducing CCR4 expression
which promoted interleukin-22-producing group 3 innate lymphoid cell
migration into the lungs, thereby enhancing lung immunity; importantly,
CD103+CD11b+DCs recognition of the
gut microbiota is required to initiate this process64.
Furthermore, the high mortality of pulmonary viral infections in
antibiotic-exposed mice may be due to immune compromise caused by
dysbiosis of the gut microbiota, leading to an increase in lung
interferon-γ, interleukin-6, and
CCL2 and a decrease in Treg cells65.
These data suggest that the gut-lung axis links the bidirectional
crosstalk between the intestine and lung. Microbiota dysbiosis in either
side of the gut and lung is likely to have potentially dramatic impacts
on the other side via the gut-lung axis. Given that previous studies
have examined the association between dysbiosis of the lung microbiota
with the occurrence and development of BPD66,67, we
have constructed a lung microbiota-gut
microbiota-BPD triangle, as shown
in Figure 3 . We propose that each factor in the triangle is
probably strongly interrelated. Hence, it is not difficult to infer that
maintaining the stability of the host’s entire microbiota has profound
implications for preventing or improving BPD.
Although the function of the gut-lung axis in other respiratory diseases
has been well-defined, the specific mechanisms of how the gut microbiota
affects the lung via the gut-lung axis in BPD have been investigated
less. Future directions exploring more experimental data in relation to
the gut-lung axis in BPD may be required to further explain this complex
area. Fully grasping this relationship is imperative as new potential
therapeutic targets for BPD may be elucidated.