背景:肠道共生菌的丰度和多样性影响全身免疫,并影响疾病易感性和严重程度。例如,短链脂肪酸(SCFA)发酵细菌在生命早期(人和小鼠)的损失与包括肺在内的外周组织中增强的2型免疫应答相关。
目的:我们的目的是揭示微生物组依赖的细胞和分子机制,驱动对2型过敏性肺病的易感性增强。
方法:我们使用低剂量万古霉素在野生型小鼠(Vanc-dys小鼠)中选择性消耗SCFA发酵细菌。然后,我们检查了有和没有SCFA补充的先天性和适应性免疫细胞谱系的频率和激活状态。最后,我们使用ILC2缺陷和信号转导和转录激活因子6(STAT6)缺陷的转基因小鼠品系来描绘导致过敏性疾病易感性增强的细胞和细胞因子途径.
结果:Vanc-dys小鼠的肺ILC2增加2倍,导致白细胞介素(IL)-2,-5和-13水平升高。此外,在IL-33治疗后,Vanc-dys肺ILC2显示出产生高水平IL-4的新能力。这些扩增和引发的ILC2驱动B1细胞扩增和IL-4依赖性IgE的产生,反过来,导致过敏性炎症加剧。重要的是,Vanc-dys小鼠的这些增强的肺部炎症表型通过饮食SCFA(特别是丁酸盐)的给药被逆转.
结论:SCFA调节ILC2-B1细胞-IgE轴。早期服用万古霉素,一种已知能耗尽SCFA发酵肠道细菌的抗生素,启动并放大该轴,并导致对2型过敏性肺病的终生易感性增强。
BACKGROUND: The abundance and diversity of intestinal commensal bacteria influence systemic immunity with impact on disease susceptibility and severity. For example, loss of short chain fatty acid (SCFA)-fermenting bacteria in early life (humans and mice) is associated with enhanced type 2 immune responses in peripheral tissues including the lung.
OBJECTIVE: Our goal was to reveal the microbiome-dependent cellular and molecular mechanisms driving enhanced susceptibility to type 2 allergic lung disease.
METHODS: We used low-dose vancomycin to selectively deplete SCFA-fermenting bacteria in wild-type mice. We then examined the frequency and activation status of innate and adaptive immune cell lineages with and without SCFA supplementation. Finally, we used
ILC2-deficient and signal transducer and activator of transcription 6 (STAT6)-deficient transgenic mouse strains to delineate the cellular and cytokine pathways leading to enhanced allergic disease susceptibility.
RESULTS: Mice with vancomycin-induced dysbiosis exhibited a 2-fold increase in lung
ILC2 primed to produce elevated levels of IL-2, -5, and -13. In addition, upon IL-33 inhalation, mouse lung
ILC2 displayed a novel ability to produce high levels of IL-4. These expanded and primed ILC2s drove B1 cell expansion and IL-4-dependent production of IgE that in turn led to exacerbated allergic inflammation. Importantly, these enhanced lung inflammatory phenotypes in mice with vancomycin-induced dysbiosis were reversed by administration of dietary SCFA (specifically butyrate).
CONCLUSIONS: SCFAs regulate an
ILC2-B1 cell-IgE axis. Early-life administration of vancomycin, an antibiotic known to deplete SCFA-fermenting gut bacteria, primes and amplifies this axis and leads to lifelong enhanced susceptibility to type 2 allergic lung disease.