The Microbiota Affects the Development of the Lung Vascular Tree in Rats

Rationale: There is a link between the microbiota and various respiratory diseases. We hypothesized that certain bacteria and their metabolites may influence the development of the lung vascular tree. Methods: We compared Fischer male axenic rats with conventional rats from day 1 to day 28 after birth using immunohistochemistry and western-blot. Quantification of alveolar and vascular wall thickness, alveolar partition, and markers was performed using the machine learning-based IPSDK software. Results: Axenic rats showed numerous lung structural abnormalities such as increased septal and alveolar wall thickness associated with increased interstitial cellularity, reduction in the number of alveoli, and increase in HIF-1 alpha expression from day 1 to day 7, suggesting reduction in gas exchange. They also had huge diffuse inflammatory cellular infiltrates of T and B lymphoid - and myeloid cells until day 7, which were decreased thereafter but reorganized into foci resembling tertiary lymphoid structures from day 14 onward, suggesting an immune response to a local (self-)antigen. Ki-67 and PCNA revealed a significant increase in proliferating cells in vessels, bronchi, and alveolar septa in axenic rats. The number of muscularized arterioles was significantly increased in axenic rats at early postnatal times, suggesting vascular remodeling. Conclusion: Axenic rats showed reduction in pulmonary exchange surface, muscularization of small pulmonary arteries, infiltration and proliferation of myeloid and lymphoid cells in the alveolar and vascular walls at an early stage after birth, and persistent lymphoid neogenesis, suggesting a potential impact of dysbiosis on lung architecture and the vascular tree.