Abstract：
OBJECTIVE: Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against Streptococcus pneumoniae infections.
METHODS: We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumoniae. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses.
RESULTS: We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-α and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose S. pneumoniae.
CONCLUSIONS: This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut-lung axis in bacterial infections.
METHODS: We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumoniae. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses.
RESULTS: We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-α and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose S. pneumoniae.
CONCLUSIONS: This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut-lung axis in bacterial infections.
摘要：
目的：全球范围内，肺炎的死亡人数超过任何其他传染病。肠道微生物群支持局部粘膜免疫，并且越来越被认为是全身免疫系统的重要调节剂。肠道菌群在细菌性肺炎中的确切作用，然而,是未知的。这里,我们研究了肠道菌群在宿主防御肺炎链球菌感染中的功能.
方法：我们耗尽了C57BL/6小鼠的肠道微生物群，随后用肺炎链球菌鼻内感染它们。然后，我们进行了存活和粪便微生物群移植（FMT）实验，并测量了炎症和肺泡巨噬细胞全基因组反应的参数。
结果：我们发现肠道菌群在肺炎球菌肺炎期间保护宿主，正如细菌传播增加所反映的那样，炎症,与对照组相比，微生物群耗尽小鼠的器官损伤和死亡率。肺炎球菌感染后6小时，肠道微生物群耗尽的小鼠中的FMT导致肺部细菌计数，肿瘤坏死因子-α和白介素-10水平正常化。肺泡巨噬细胞的全基因组图谱显示，在没有健康肠道微生物群的情况下，代谢途径上调。这种上调与细胞反应性的改变有关，反映对脂多糖和脂磷壁酸的反应性降低。与对照组相比，来自肠道微生物群耗尽小鼠的肺泡巨噬细胞对肺炎链球菌的吞噬能力减弱.
结论：本研究确定肠道微生物群是肺炎球菌肺炎期间的保护性介质。肠道菌群增强初级肺泡巨噬细胞功能。新的治疗策略可以在细菌感染中利用肠-肺轴。
方法：我们耗尽了C57BL/6小鼠的肠道微生物群，随后用肺炎链球菌鼻内感染它们。然后，我们进行了存活和粪便微生物群移植（FMT）实验，并测量了炎症和肺泡巨噬细胞全基因组反应的参数。
结果：我们发现肠道菌群在肺炎球菌肺炎期间保护宿主，正如细菌传播增加所反映的那样，炎症,与对照组相比，微生物群耗尽小鼠的器官损伤和死亡率。肺炎球菌感染后6小时，肠道微生物群耗尽的小鼠中的FMT导致肺部细菌计数，肿瘤坏死因子-α和白介素-10水平正常化。肺泡巨噬细胞的全基因组图谱显示，在没有健康肠道微生物群的情况下，代谢途径上调。这种上调与细胞反应性的改变有关，反映对脂多糖和脂磷壁酸的反应性降低。与对照组相比，来自肠道微生物群耗尽小鼠的肺泡巨噬细胞对肺炎链球菌的吞噬能力减弱.
结论：本研究确定肠道微生物群是肺炎球菌肺炎期间的保护性介质。肠道菌群增强初级肺泡巨噬细胞功能。新的治疗策略可以在细菌感染中利用肠-肺轴。
