Epithelial barrier defects are implicated in the pathogenesis of inflammatory bowel disease (IBD); however, the role of microbiome dysbiosis and the cytokine networks orchestrating chronic intestinal inflammation in response to barrier impairment remain poorly understood. Here, we showed that altered Schaedler flora (ASF), a benign minimal microbiota, was sufficient to trigger colitis in a mouse model of intestinal barrier impairment. Colitis development required myeloid-cell-specific adaptor protein MyD88 signaling and was orchestrated by the cytokines IL-12, IL-23, and IFN-γ. Colon inflammation was driven by IL-12 during the early stages of the disease, but as the mice aged, the pathology shifted toward an IL-23-dependent inflammatory response driving disease chronicity. These findings reveal that IL-12 and IL-23 act in a temporally distinct, biphasic manner to induce microbiota-driven chronic intestinal inflammation. Similar mechanisms might contribute to the pathogenesis of IBD particularly in patients with underlying intestinal barrier defects.

中文翻译：

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细胞因子IL-12和IL-23的暂时不同功能在响应肠屏障功能障碍时驱动慢性结肠炎。

上皮屏障缺损与炎症性肠病（IBD）的发病机理有关。然而，微生物组功能失调和细胞因子网络协调对屏障障碍作出反应的慢性肠道炎症的作用仍知之甚少。在这里，我们显示了改变的Schaedler菌群（ASF），一种良性的最小菌群，足以在肠壁屏障受损的小鼠模型中引发结肠炎。结肠炎的发展需要髓样细胞特异性衔接蛋白MyD88信号传导，并由细胞因子IL-12，IL-23和IFN-γ共同调控。在疾病的早期阶段，结肠炎是由IL-12引起的，但是随着小鼠的衰老，病理学转向了依赖IL-23的炎症反应，从而驱动了疾病的慢性发展。这些发现表明，IL-12和IL-23的作用在时间上是截然不同的，以双相方式诱发微生物群驱动的慢性肠道炎症。类似的机制可能有助于IBD的发病机理，特别是在具有潜在的肠屏障缺陷的患者中。