In this study we found that antibiotic-induced intestinal dysbacteriosis prior to hyperoxia exposure increased the susceptibility of mouse BPD, evidenced by decreased RAC, increased MLI and increased mortality in the antibiotics treated BPD mice. These findings supported the previous hypothesis that the preterm infants who frequently received antibiotics therapy often developed more severe BPD.
BPD is the most common complicating disease of premature birth. Neonates with BPD usually subjected to respiratory sequelae [20, 21]. BPD remains a substantial challenge to the neonatologist. Therefore, in this study, we researched the potential mechanisms of BPD through animal experiments.
Infants in NICU often receive antibiotics treatment. Antibiotics change the composition of gut microbiota. Gut microbiota composition is related to the immunological response. There are increasing evidences that support the concept of cross-talk between the gut microbiota and the lung. For example, Intestinal dysbacteriosis in mice results in abnormal airway allergic responses. Microbiota depletion aggravate ventilator-induced lung injury. These evidences supported that the gut microbiota may affect the lung mucosa by influencing the immunological response. But the participation of antibiotic-induced intestinal dysbacteriosis in the progression of BPD remains unclear. This study researched the effect of intestinal dysbacteriosis on hyperoxia exposure induced the BPD mouse model.
To investigate this interaction, neonates were therapied with a broad-spectrum antibiotic regimen for the induction of intestinal dysbacteriosis. The administration of antibiotics was showed significantly changed the composition of gut microbiota in neonatal mice.We found the relative abundance of the phylum Firmicutes, Bacteroidetes and the genus Bacteroides and norank_f__Muribaculaceae significantly decreased in the antibiotics treated mice. In contrast, the relative abundance of the phylum Proteobacteria and the genus Citrobacter and unclassified_f__Enterobacteriaceae significantly increased in the antibiotics treated mice. The findings were consistent with the previous studies, which showed that antibiotics induced intestinal dysbacteriosis causing decreased relative abundance of phylum Bacteroidetes and Firmicutes and increased relative abundance of Proteobacteria [24, 25].
According to the previous reports, macrophage polarization may play important roles in the development of BPD [26, 27]. Activated macrophages can be M1- or M2-polarized. Modulating the M1/M2 polarization status of macrophages can affect the severity of acute inflammatory conditions of the lung. In this study, we found that antibiotics treatment promoted M1 markers iNOS expression and inhibited M2 markers Arg1 expression in the BPD mice. Hence, antibiotics treatment promoted the macrophages transformation towards pro-inflammatory M1 phenotype and inhibited the macrophages transformation towards anti-inflammatory M2 phenotype. So antibiotics treatment may promote inflammations and inhibit anti-inflammations resulting in the aggravation of BPD. Meanwhile, another study showed that after the composition of gut microbiota were changed and their metabolites were depleted during antibiotic administration, the supplementation of antibiotics with the metabolites could promote the macrophages transformation towards anti-inflammatory M2 phenotype. Based on the above evidences, we hypothesised that antibiotics treatment may aggravate the mouse BPD via modulating the M1/M2 polarization status of macrophages.
There are limitations need to be considered. Firstly, there was a relatively high mortality in the experimental mice. the reason may be that experiments were conducted in neonatal mice subjected at 2–3 d of life. Secondly, antibiotics administration may effect the results of this study, the administration of antibiotics with fecal microbiota transplants (FMT) may help us to understand the role of microbiota in the development of BPD.