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.

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