Fecal microbiota transplants (FMT) of three distinct human communities to germ-free mice exacerbated inflammation and decreased lung function in their offspring

Despite explosive rise in allergies, little is known about early life gut
microbiota effects on postnatal respiratory function. We hypothesized that
Enterobacteriaceae-dominant gut microbiota from eczemic infants increases
Type 2 inflammation and decreases lung function in transplanted mice,
while Bacteroidaceae-dominant gut microbiota from non-eczemic infants is
protective. FMT from eczemic infants “Infant A” and non-eczemic infants
“Infant B” were successfully transplanted into germ-free C57BL/6 mice
passing to offspring unchanged. Infant A and B, Adult C-human-derived
(positive control), and mouse (negative control) microbiotas all in
C57BL/6 mice were tested for effects on airway function in non-allergic
(PBS) and allergic (HDM) conditions. Baseline lung mechanics in mice with
human microbiotas (HUmicrobiota) were significantly impaired compared to
mouse microbiota controls (MOmicrobiota) with or without HDM; Respiratory
system resistance (Rrs) was increased (p< 0.05-p<0.01) and
Respiratory system compliance (Crs) was decreased
(p<0.05-p<0.01). HUmicrobiota mice showed statistically
significant impairment compared to MOmicrobiota mice in lung parameters
Rrs, Ers, Rn, and G at baseline, and at multiple Mch doses with baseline
removed. Impairment manifested as increased small airway resistance and
tissue resistance. HDM significantly elevated IL-4, eosinophils, lung
inflammation and mucus cell metaplasia and decreased macrophages and lung
function (p<0.05) in mice of all microbiotas, yet each HUmicrobiota
produced distinct features. Infant B and Adult C mice had elevated basal
levels of total IgE compared to MOmicrobiota and Infant A mice
(p<0.05). In HUmicrobiota mice given HDM, only Adult C had elevated
IL-5 and IL-13 (p<0.05), only Adult C and Infant B mice had
elevated neutrophils (p<0.05) and only Infant A had elevated
lymphocytes (p<0.01).

尽管过敏症的发病率呈爆发式增长，学界对生命早期肠道微生物群（gut microbiota）影响产后呼吸功能的相关机制仍知之甚少。我们提出如下假说：特应性皮炎婴儿体内以肠杆菌科（Enterobacteriaceae）为主导的肠道微生物群，可使接受移植的小鼠出现2型炎症反应增强、肺功能下降的表型；而非特应性皮炎婴儿体内以拟杆菌科（Bacteroidaceae）为主导的肠道微生物群，则对肺功能具有保护作用。我们成功将特应性皮炎婴儿“婴儿A”与非特应性皮炎婴儿“婴儿B”的粪便菌群移植（Fecal Microbiota Transplantation, FMT）样本移植至无菌C57BL/6小鼠（germ-free C57BL/6 mice）体内，且移植后的菌群可稳定传递至子代且未发生改变。我们在C57BL/6小鼠体内分别定植了婴儿A、婴儿B、成人C来源的人类菌群（HUmicrobiota，阳性对照）以及小鼠自身菌群（MOmicrobiota，阴性对照），并检测这些菌群在非致敏（PBS处理）与致敏（屋尘螨HDM处理）条件下对气道功能的影响。与定植小鼠自身菌群的对照组相比，定植人类菌群的小鼠无论是否经HDM致敏，其基础肺力学指标均显著受损：呼吸系统阻力（Respiratory System Resistance, Rrs）升高（p<0.05~p<0.01），呼吸系统顺应性（Respiratory System Compliance, Crs）降低（p<0.05~p<0.01）。在基础状态以及去除基础值后的多个乙酰甲胆碱（methacholine, Mch）剂量下，定植人类菌群的小鼠在肺功能参数Rrs、Ers、Rn以及G上的表现均显著差于定植小鼠自身菌群的小鼠，其损伤表现为小气道阻力与组织阻力升高。经HDM致敏后，所有菌群定植组小鼠的白细胞介素4（IL-4）、嗜酸性粒细胞水平、肺部炎症程度以及黏液细胞化生均显著升高，巨噬细胞水平与肺功能则显著下降（p<0.05）；但不同人类菌群定植组呈现出各异的特征。与定植小鼠自身菌群组以及婴儿A定植组相比，婴儿B组与成人C组小鼠的总IgE基础水平显著升高（p<0.05）。在经HDM致敏的人类菌群定植小鼠中，仅成人C组小鼠的白细胞介素5（IL-5）与白细胞介素13（IL-13）水平显著升高（p<0.05），仅成人C组与婴儿B组小鼠的中性粒细胞水平显著升高（p<0.05），而仅婴儿A组小鼠的淋巴细胞水平显著升高（p<0.01）。