School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
J Allergy Clin Immunol. 2024 Nov;154(5):1260-1276.e9. doi: 10.1016/j.jaci.2024.07.023. Epub 2024 Aug 10.
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.
Our goal was to reveal the microbiome-dependent cellular and molecular mechanisms driving enhanced susceptibility to type 2 allergic lung disease.
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.
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).
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.
肠道共生菌的丰度和多样性影响全身免疫，从而影响疾病的易感性和严重程度。例如，早期生活（人类和小鼠）中短链脂肪酸（SCFA）发酵细菌的丧失与外周组织（包括肺部）中 2 型免疫反应的增强有关。
我们的目标是揭示依赖微生物组的细胞和分子机制，这些机制驱动对 2 型过敏性肺部疾病的易感性增加。
我们使用低剂量万古霉素选择性地耗尽野生型小鼠中的 SCFA 发酵细菌。然后，我们检查了有无 SCFA 补充时固有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）缺陷转基因小鼠品系来描绘导致增强过敏易感性的细胞和细胞因子途径。
万古霉素诱导的肠道菌群失调小鼠的肺部 ILC2 数量增加了 2 倍，这些 ILC2 被预先激活以产生高水平的 IL-2、-5 和 -13。此外，在吸入 IL-33 后，小鼠肺部 ILC2 显示出产生高水平 IL-4 的新能力。这些扩增和预激活的 ILC2 驱动 B1 细胞扩增和 IL-4 依赖性 IgE 产生，从而导致过敏炎症加剧。重要的是，通过给予饮食 SCFA（特别是丁酸盐），可逆转万古霉素诱导的肠道菌群失调小鼠的这些增强的肺部炎症表型。
SCFAs 调节 ILC2-B1 细胞-IgE 轴。已知可耗尽 SCFA 发酵肠道细菌的抗生素万古霉素的早期给药会启动和放大该轴，并导致终生对 2 型过敏性肺部疾病的易感性增加。
