Role of epithelial ROS signaling in mediating psychological stress-induced mucosal dysfunction and colitis predisposition

项目摘要/摘要： 炎症性肠病(IBD)在美国正变得越来越普遍，并代表着一种主要的社会健康 担忧。暴露于心理社会应激源增加了遗传性IBD发病的可能性 易感个体，暗示了IBD病因框架中的脑-肠轴。新兴的工作领域 已经确定，压力对肠道微生物区系的破坏(即生物失调)可能是最接近的 应激性IBD易感性的原因。这包括来自我们实验室的数据，我们在那里展示了一种 小鼠适应病原菌对小鼠结肠炎的定植和诱导作用更强 通过暴露在慢性社会失败应激源下的小鼠的微生物群。此外，我们新的初步数据 有证据表明，压力会加重慢性免疫(T细胞)结肠炎。然而，肠子是如何 微生物区系和粘膜层对应激源的反应失调，以及这些变化的原因 易感加重结肠炎，目前尚不清楚。我们最近证明，压力会导致大范围的变化 肠道上皮细胞(IEC)活动与肠道微生物区系功能和纤细的变化密切相关 粘液层。在IECS中观察到的这些变化中，我们的初步数据表明，活性氧 IECS的物种(ROS)产生能力可能是应激诱导的生物失调的最直接原因 粘膜破裂。在基线时，无菌(GF)小鼠的IECS中没有应激迹象，因此暗示 IEC响应中的微生物区系。然而，IECs仍然准备好对体外培养的细胞做出不同的反应。 细菌挑战(证明为ROS生成酶双氧化酶的表达增加 (DUOX2)，表明宿主应激信号分子和肠道微生物区系共同参与了 规范IEC活动。有趣的是，IECS中DUOX2和ROS活性的上调对应于 能够降解粘液的耐ROS细菌的扩张。这些数据使我们建立了一个 这一提议背后的凝聚力框架，使应激激素“启动”IEC对内源性的反应 微生物区系信号/黏附通过增加ROS生成。这增强了粘膜中的ROS活性 INTERFACE为抵抗ROS活性并存活的粘膜相关微生物创造了独特的生态位 通过降解通常对内源微生物和病原体都具有屏障的粘液多糖。 我们假设，这种IEC导向的、抵抗ROS的、粘液降解的内源微生物的扩张是 暴露在长期、持续的压力下的生物体对IBD易感性的基础是什么。

PROJECT SUMMARY/ABSTRACT: Inflammatory bowel diseases (IBD) are becoming more prevalent in the US and represent a major societal health concern. Exposure to psychosocial stressors increases the likelihood of developing IBD in genetically predisposed individuals, implicating a brain-gut axis in the IBD etiological framework. An emerging line of work has established that stress-induced disruptions to the gut microbiota (i.e. dysbiosis) may be the most proximate cause of stress-induced IBD predisposition. This includes data from our laboratory where we showed that a mouse adaptive pathogen (C. rodentium) was more effective at colonizing and inducing colitis in mice colonized by a microbiota from mice exposed to a chronic social defeat stressor. Moreover, our new preliminary data provides evidence stress exacerbates chronic, immune mediated (T-cell) colitis. However, how the gut microbiota and mucosal layer becomes dysregulated in response to stressors and why those changes predispose worsened colitis, is not yet understood. We recently demonstrated that stress induces large shifts in intestinal epithelial cell (IEC) activity that tightly corresponded to changes in gut microbiota function and thinning of the mucus layer. Of those changes observed in IECs, our preliminary data indicate that the reactive-oxygen species (ROS)-generating capacity of IECs may be the most proximate causes of stress-induced dysbiosis and mucosal disruption. Signs of stress in IECs were absent in germ-free (GF) mice at baseline, thus implicating the microbiota in IEC responsiveness. Nevertheless, IECs were still primed to respond differentially to an ex vivo bacterial challenge (evidenced by an increased expression in the ROS-generating enzyme dual oxidase (DUOX2), suggesting that host stress signaling molecules and the gut microbiota are together involved in regulating IEC activity. Intriguingly, the upregulation in DUOX2 and ROS activity in IECs corresponded to expansion of ROS-resistant bacteria that are capable of mucus degradation. These data led us to build a cohesive framework underlying this proposal, whereby stress hormones ‘prime’ IECs to respond to endogenous microbiota signaling/adhesion through heightened ROS generation. This enhanced ROS activity at the mucosal interface creates a unique niche for mucosal associated microbes that are resistant to ROS activity and survive by degrading mucus glycans that normally provide a barrier against both endogenous microbes and pathogens. We hypothesize that this IEC-directed expansion of ROS-resistant, mucus-degrading endogenous microbes is what underlies IBD susceptibility in organisms exposed to chronic, unabated stress.