ABSTRACT

Changes in the intestinal microbiota indirectly impact the health of mucosa distal to the intestine, particularly the respiratory tract. However, the effects of intestinal microbiota dysbiosis on the regulation of respiratory syncytial virus (RSV) infection are not clear. In this study, we examined the effects of altering the intestinal microbiota on the pulmonary immune response against RSV infection. BALB/c mice were treated with streptomycin before infection with RSV to study the altered immune response. The ingestion of streptomycin led to a marked alteration in the intestinal microbiota with a reduced abundance of Lactobacillus and Clostridium genera, followed by greatly aggravated pulmonary inflammation in response to RSV infection. This aggravated inflammation was associated with a dysregulated immune response against RSV infection, characterized by the increased expression of IFN-γ and IL-17 and increased pulmonary M1-like macrophage polarization, and decreased expression of IL-5. Supplementation of Clostridium butyricum (CB) prevented aggravated inflammation and the dysregulated immune response characterized by greater M2 polarization of pulmonary macrophages and decreased release of IFN-γ and IL-17 as well as increased IL-5 levels. Furthermore, in vitro and in vivo experiments identified that butyrate, the main metabolite produced by CB, promoted M2 polarization of macrophages in RSV-infected mice exposed to streptomycin. Together, these results demonstrate the mechanism by which intestinal microbiota modulate the pulmonary immune response to RSV infection.

摘要

肠道微生物群的变化间接影响肠道远端黏膜的健康，尤其是呼吸道。然而，肠道菌群失调对呼吸道合胞病毒（RSV）感染的调节作用尚不清楚。在这项研究中，我们检查了改变肠道微生物群对抵抗 RSV 感染的肺部免疫反应的影响。BALB/c 小鼠在感染 RSV 之前用链霉素处理以研究改变的免疫反应。摄入链霉素导致肠道微生物群发生显着变化，乳酸杆菌和梭状芽胞杆菌的丰度降低属，随后响应 RSV 感染大大加重了肺部炎症。这种加重的炎症与针对 RSV 感染的免疫反应失调有关，其特征是 IFN-γ 和 IL-17 的表达增加，肺 M1 样巨噬细胞极化增加，IL-5 的表达降低。补充丁酸梭菌(CB) 可防止炎症加重和免疫反应失调，其特征是肺巨噬细胞的 M2 极化更大，IFN-γ 和 IL-17 的释放减少以及 IL-5 水平升高。此外，在体外和体内实验发现，CB 产生的主要代谢物丁酸盐促进了暴露于链霉素的 RSV 感染小鼠中巨噬细胞的 M2 极化。总之，这些结果证明了肠道微生物群调节对 RSV 感染的肺部免疫反应的机制。