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.

项目总结/摘要： 炎症性肠病（IBD）在美国变得越来越普遍，代表了一种主要的社会健康问题 关心暴露于心理社会压力因素会增加遗传性IBD的可能性 易感个体，暗示IBD病因学框架中存在脑-肠轴。一个新兴的行业 已经确定，应激诱导的肠道微生物群破坏（即生态失调）可能是最接近的 压力诱发IBD的原因。这包括我们实验室的数据，我们显示， 小鼠适应性病原体（C.啮齿类）在小鼠中的定殖和诱导结肠炎方面更有效， 通过一种来自长期暴露于社交失败压力源的小鼠的微生物群。此外，我们新的初步数据显示， 提供了证据表明，压力加剧慢性免疫介导的（T细胞）结肠炎。然而，肠道如何 微生物群和粘膜层在应对压力时变得失调，以及为什么这些变化 易患结肠炎恶化，尚不清楚。我们最近证明，压力会导致 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 粘液层的一部分在IEC中观察到的这些变化中，我们的初步数据表明， IEC产生活性氧（ROS）的能力可能是应激诱导的生态失调的最直接原因， 粘膜破坏。在基线时，无菌（GF）小鼠的IEC中没有应激迹象，因此暗示了 微生物群在IEC响应中的作用。尽管如此，IEC仍然被激发以差异地响应于离体的免疫刺激。 细菌攻击（通过ROS生成酶双氧化酶的表达增加来证明 （DUOX 2），表明宿主应激信号分子和肠道微生物群共同参与了 规范IEC活动。有趣的是，IEC中DUOX 2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。这些数据使我们建立了一个 这一建议的基础是一个有凝聚力的框架，即应激激素“引导”IEC对内源性 通过增加ROS产生的微生物群信号传导/粘附。这增强了粘膜中ROS的活性， 界面为抵抗ROS活性并存活的粘膜相关微生物创造了独特的生态位 通过降解粘液聚糖，粘液聚糖通常提供对内源性微生物和病原体的屏障。 我们假设，这种IEC指导的ROS抗性、粘液降解内源性微生物的扩增是 暴露于慢性、不减压力的生物体中IBD易感性的基础是什么。