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.