Microbial reactivation of sex steroids and visceral pain

性类固醇的微生物再激活和内脏疼痛

• 批准号: 10671053
• 负责人: Meenakshi Rao
• 金额: $ 56.94万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671053
• 关键词: Abdominal Pain; Address; Affect; Afferent Neurons; Androgen Receptor; Androgens; Antibiotics; Bacteria; Beta-glucuronidase; Bile fluid; Central Nervous System; Chemistry; Colon; Colorectal; Communication; Data; Diagnosis; Digestive System Disorders; Disease; Enzyme Inhibitor Drugs; Enzymes; Esthesia; Excretory function; Exhibits; Female; Gastrointestinal Diseases; Genetic; Germ-Free; Glucuronides; Gnotobiotic; Goals; Gonadal Steroid Hormones; High Prevalence; Homeostasis; Hormones; Human; Hypersensitivity; In Vitro; Individual; Inflammatory; Inflammatory Bowel Diseases; Intestines; Irritable Bowel Syndrome; Link; Liver; Mediating; Mediator; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Natural regeneration; Nerve; Neurosecretory Systems; Nociceptors; Pain; Pain Disorder; Pathway interactions; Patients; Peripheral; Population; Probiotics; Research; Research Personnel; Rodent; Role; Sensory Thresholds; Severities; Sex Differences; Signal Transduction; Spinal; Stanolone; Steroids; Stimulus; Symptoms; Testing; Testosterone; Vertebral column; Visceral; Visceral Afferent Neuron; Visceral Afferents; Visceral pain; Woman; Work; antinociception; cellular targeting; chronic abdominal pain; chronic pain; commensal microbes; common symptom; dysbiosis; effective therapy; enzyme activity; experience; gut microbes; gut microbiota; gut-brain axis; healing; host-microbe interactions; in vivo; inflammatory pain; inhibitor; innovation; male; men; microbial; microbiota; mouse model; neuronal excitability; normal microbiota; novel; pain sensation; pain signal; programs; protective effect; response; sex; small molecule; steroid hormone; therapeutic target

PROJECT SUMMARY Abdominal pain is a common symptom of digestive disease that is poorly addressed by existing therapies. Probiotics are widely used to treat abdominal pain even though most studies that have examined their effects have had disappointing results. A more effective strategy might be to stimulate specific pathways of microbes already present in the gut that benefit the host. The overarching goal of this proposal is to determine if a microbial pathway that reactivates steroids in the gut lumen normally regulates the activity of sensory neurons that mediate visceral sensation, and whether this pathway can be manipulated to influence abdominal pain. Abdominal pain is mediated by visceral afferents, primary sensory neurons located outside the gut that communicate information from the gut to the central nervous system. Prior studies suggest that commensal microbiota normally limit visceral afferent sensitivity. Depletion of commensal microbes causes exaggerated responses to colorectal distention, evidence that visceral afferents become hypersensitive to non-noxious stimuli in the absence of microbes. The full extent of microbial effects on visceral pain and the signals that mediate them, however, are largely unclear. Androgens, steroid hormones that circulate at higher levels in males than females, are compelling candidates. Androgens are anti-nociceptive in somatic pain and emerging evidence suggests they have similar effects in visceral pain. In irritable bowel syndrome (IBS), a disorder defined by chronic abdominal pain, we found that low androgen levels were associated with both diagnosis and symptom severity in males and females. Furthermore, androgen homeostasis has clear links to gut microbiota. Like other steroids, androgens are inactivated by glucuronidation in the liver and excreted into bile. In the gut lumen, these inactive forms become substrates for microbial β-glucuronidase enzymes (GUS) that remove the glucuronide moieties, regenerating a large pool of active androgens. Thus, androgen reactivation could be a key mechanism by which commensal microbes limit visceral hypersensitivity, linking previous observations. The central hypothesis of this proposal is that androgens reactivated by microbial GUS signal directly to host visceral afferent neurons to limit peripheral sensitization and pain. First, we will establish the independent effects of commensal microbes, microbial GUS activity, and androgen signaling to visceral afferent neurons on abdominal pain. Then, we will test for mechanistic links between each component. Incorporating genetic and gnotobiotic mouse models as well novel inhibitors of microbial GUS enzymes developed by the co-I, a leader in GUS chemistry, this innovative project moves the PI's research program into new directions of visceral pain and host-microbe interactions. The impact of this work will be to advance the understanding of visceral sensation and generate key evidence for new rational therapeutic targets in abdominal pain.

项目摘要 腹痛是消化疾病的常见症状，现有疗法解决。 益生菌被广泛用于治疗腹痛，尽管大多数研究都检查了其作用 结果令人失望。更有效的策略可能是刺激微生物的特定途径 在肠道中已经有使主机受益的。该提案的总体目标是确定是否a 在肠道中反应类固醇的微生物途径通常调节感觉神经元的活性 这种介导内脏的感觉，以及是否可以操纵这种途径以影响腹痛。 腹痛是由内脏传入，位于肠道外的主要感觉神经元介导的 从肠道到中枢神经系统的通信信息。先前的研究表明共生 微生物群通常限制内脏传入敏感性。共生微生物的耗尽会导致夸大 对结直肠距离的反应，表明内脏传入对非敏感的过敏的证据 在没有微生物的情况下刺激。微生物对内脏疼痛的全部影响以及信号 但是，调解它们在很大程度上不清楚。雄激素，类固醇激素，以较高的水平循环 男性比女性是令人信服的候选人。雄激素在躯体疼痛和出现中具有抗伤害感受 有证据表明它们在内脏疼痛中具有相似的影响。在肠易激综合症（IBS）中 由慢性腹痛定义，我们发现低雄激素水平与诊断和 男性和女性的症状严重程度。此外，雄激素稳态与肠道微生物群具有明显的联系。 像其他类固醇一样，雄激素被肝脏中的麸质被灭活，并将其独家分成胆汁。在肠道里 管腔，这些非活性形式成为微生物β-葡萄糖醛酸酶（GUS）的底物，以去除 葡萄糖醛酸部分，可再生大量活跃的雄激素。那，雄激素重新激活可能是 共同微生物限制内脏超敏反应的关键机制，与先前的观察联系起来。 该提议的中心假设是，由微生物GUS信号重新激活的雄激素直接激活至宿主 内脏传入的神经元以限制外周敏感性和疼痛。首先，我们将建立独立 共生微生物，微生物GUS活性和雄激素信号对内脏传入神经元的影响 腹痛。然后，我们将测试每个组件之间的机械链接。结合遗传和 Gnotobiotic小鼠模型以及由Co-I开发的微生物GUS酶的新型抑制剂， GUS化学，这个创新的项目将PI的研究计划移至内脏疼痛的新方向 和宿主 - 微叶片相互作用。这项工作的影响将是提高对内脏的理解 感觉并为腹痛中新的理性治疗靶标的关键证据。