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

上皮ROS信号在介导心理应激引起的粘膜功能障碍和结肠炎易感性中的作用

• 批准号: 10521707
• 负责人: Jacob Matthew Allen
• 金额: $ 68.55万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-31 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521707
• 关键词: Ablation; Adhesions; Anaerobic Bacteria; Animals; Bacteria; Bacteroides; Biological Factors; Catecholamines; Cell Line; Cell physiology; Cellular Stress; Chronic; Citrobacter; Citrobacter rodentium; Colitis; Colon; Corticotropin-Releasing Hormone; Data; Disease; Disease susceptibility; Enterobacteriaceae; Environment; Enzymes; Epithelial; Epithelial Cells; Etiology; Exhibits; Exposure to; Family; Female; Flagellin; Functional disorder; Generations; Genetic Predisposition to Disease; Germ Cells; Germ-Free; Glucocorticoids; Growth; Gut Mucosa; Health; Hormone Receptor; Hormones; Human; Hydrogen Peroxide; Immune; Immune response; Immune system; Incidence; Individual; Infection; Infectious colitis; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Laboratories; Link; Mediating; Metagenomics; Microbe; Mucins; Mucolytics; Mucous Membrane; Mucous body substance; Mus; NADP; Neuraminidase; Organism; Outcome; Oxidases; Pathway interactions; Patients; Pharmacology; Physiology; Polysaccharides; Predisposition; Production; Psychological Stress; Psychosocial Stress; Reactive Oxygen Species; Resistance; Risk; Role; Severities; Sialic Acids; Side; Signal Transduction; Signaling Molecule; Stress; Structure; Sympathetic Nervous System; T-Lymphocyte; Testing; Thinness; Up-Regulation; Work; antimicrobial; bacterial resistance; catalase; cohesion; colon microbiota; dysbiosis; enteric pathogen; experimental study; gastrointestinal epithelium; gut microbes; gut microbiota; gut-brain axis; host microbiota; host-microbe interactions; hypothalamic-pituitary-adrenal axis; intestinal epithelium; male; member; microbial; microbial community; microbiome; microbiome analysis; microbiota; mouse model; mucosal microbiota; novel; pathobiont; pathogen; pathogenic microbe; psychosocial stressors; response; restraint stress; social defeat; social stress; stressor; targeted treatment; villin

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.

项目概要/摘要： 炎症性肠病（IBD）在美国变得越来越普遍，并代表了一个主要的社会健康问题 忧虑。暴露于社会心理压力源会增加遗传性 IBD 的可能性 易感个体，暗示 IBD 病因学框架中存在脑肠轴。新兴的工作领域 已经确定压力引起的肠道微生物群破坏（即菌群失调）可能是最直接的影响 压力诱发 IBD 易感性的原因。这包括我们实验室的数据，我们表明 小鼠适应性病原体（C. rodentium）在定植小鼠中更有效地定植并诱导结肠炎 是由暴露于慢性社交挫败压力源的小鼠体内的微生物群产生的。此外，我们的新初步数据 提供证据表明压力会加剧慢性免疫介导（T 细胞）结肠炎。然而，肠道如何 微生物群和粘膜层因应激源而变得失调以及这些变化的原因 诱发结肠炎恶化，目前尚不清楚。我们最近证明，压力会引起巨大的转变 肠上皮细胞（IEC）活性与肠道微生物群功能和变薄的变化密切相关 的粘液层。在 IEC 中观察到的这些变化中，我们的初步数据表明活性氧 IEC 的物种（ROS）生成能力可能是应激引起的生态失调的最直接原因 粘膜破坏。在基线时，无菌 (GF) 小鼠中 IEC 不存在应激迹象，因此暗示 IEC 反应性中的微生物群。尽管如此，IEC 仍准备好对离体反应做出不同的反应。 细菌挑战（ROS 生成酶双氧化酶表达增加证明 （DUOX2），表明宿主应激信号分子和肠道微生物群共同参与 规范 IEC 活动。有趣的是，IEC 中 DUOX2 和 ROS 活性的上调对应于 能够降解粘液的 ROS 抗性细菌的扩增。这些数据引导我们建立一个 该提案背后的凝聚力框架，其中应激激素“启动”IEC以应对内源性 通过增加 ROS 生成来增强微生物群信号传导/粘附。这增强了粘膜处的ROS活性 界面为粘膜相关微生物创造了一个独特的生态位，这些微生物能够抵抗 ROS 活性并存活下来 通过降解通常提供抵抗内源微生物和病原体屏障的粘液聚糖。 我们假设 IEC 指导的 ROS 抗性、粘液降解内源微生物的扩张是 暴露于长期、未减弱的压力的生物体易感 IBD 的原因是什么。