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: 10667614
• 负责人: Jacob Matthew Allen
• 金额: $ 66.56万
• 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/10667614
• 关键词: Ablation; Adhesions; Anaerobic Bacteria; Animals; Bacteria; Bacteroides; Biological Factors; Catecholamines; Cell Line; Cell physiology; Cellular Stress; Chronic; Citrobacter rodentium; Colitis; Colon; Corticotropin-Releasing Hormone; Data; Disease; Disease susceptibility; Enterobacteriaceae; Environment; Enzymes; Epithelial Cells; Epithelium; 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; Physiology; Polysaccharides; Predisposition; Production; Psychological Stress; Psychosocial Stress; Reactive Oxygen Species; Resistance; Risk; Role; Severities; Sialic Acids; Side; Signal Transduction; Signaling Molecule; Stress; Structure; Surface; Sympathetic Nervous System; T-Lymphocyte; Testing; Thinness; Up-Regulation; Work; antimicrobial; bacterial resistance; catalase; colon microbiota; dysbiosis; enteric pathogen; experimental study; gastrointestinal epithelium; glycosylation; 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; pharmacologic; 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.

项目摘要/摘要： 在美国，炎症性肠病（IBD）变得越来越普遍，代表了主要的社会健康 忧虑。暴露于社会心理压力源增加了开发IBD的可能性 诱发的个体，在IBD病因框架中暗示了脑肠轴。新兴的工作 已经确定应力引起的肠道菌群中断（即营养不良）可能是最近端的 压力引起的IBD倾向的原因。这包括来自我们实验室的数据，我们表明 小鼠自适应病原体（C. rodentium）在定植的小鼠定殖和诱导结肠炎方面更有效 由暴露于慢性社会失败压力源的小鼠的微生物群。而且，我们的新初步数据 提供证据应力加剧慢性，免疫介导的（T细胞）结肠炎。但是，肠道如何 微生物群和粘膜层因应激源而失调，以及这些变化的原因 尚未了解易感性结肠炎。我们最近证明，压力会引起大幅变化 肠上皮细胞（IEC）活性与肠道菌群功能的变化紧密相对应 粘液层。在IEC中观察到的这些变化中，我们的初步数据表明反应性氧 IEC的物种（ROS）生成能力可能是压力引起的营养不良的最直接原因 粘膜破坏。在基线时，无菌（GF）小鼠中没有IEC的压力迹象，因此隐含 IEC反应性中的微生物群。然而，IEC仍被启示以对离体的反应不同 细菌挑战（通过在ROS-生成酶双重氧化酶中表达增加证明 （Duox2），表明宿主应力信号分子和肠道菌群都参与 调节IEC活动。有趣的是，IEC中DUOX2和ROS活性的上调与 能够降解粘液的抗ROS抗性细菌的膨胀。这些数据导致我们构建 该提案的基础框架的凝聚力框架，在该框架中，强调荷尔蒙“ Prime” IEC对内源性做出反应 微生物群信号传导/粘附通过增强的ROS产生。这种增强的ROS活性在粘膜下 界面为抗粘膜相关的微生物创建了一个独特的利基市场，该微生物对ROS活性和生存具有抗性 通过降解通常为内源性微生物和病原体提供障碍的粘液聚糖。 我们假设这种IEC指导的ROS抗粘液内源性微生物的膨胀是 IBD易感性的基础是暴露于慢性，不减压的生物体。