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: 10494428
• 负责人: Meenakshi Rao
• 金额: $ 58.92万
• 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/10494428
• 关键词: Abdominal Pain; Address; Affect; Afferent Neurons; Androgen Receptor; Androgens; Antibiotics; Bacteria; Beta-glucuronidase; Bile fluid; Chemistry; Colon; Colorectal; Data; Diagnosis; Digestive System Disorders; Disease; Enzyme Inhibitor Drugs; Enzymes; Esthesia; 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 of activation protein; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Natural regeneration; Nerve; Neuraxis; Neurosecretory Systems; Nociception; 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; Visceral; Visceral Afferent Neuron; Visceral Afferents; Visceral pain; Woman; Work; 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 腹痛是消化系统疾病的一种常见症状，现有的治疗方法对它的治疗效果很差。 益生菌被广泛用于治疗腹痛，即使大多数研究已经检查了它们的效果 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 已经存在于肠道中对宿主有益的物质本提案的总体目标是确定 在肠腔中重新激活类固醇的微生物途径通常调节感觉神经元的活性 介导内脏感觉，以及是否可以操纵这一途径来影响腹痛。 腹痛是由内脏传入神经介导的，内脏传入神经是位于肠道外的初级感觉神经元， 将信息从肠道传递到中枢神经系统。先前的研究表明， 微生物群通常限制内脏传入敏感性。共生微生物的消耗导致夸大 对结直肠扩张的反应，内脏传入神经对无害神经变得高度敏感的证据 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 然而，调解这些问题在很大程度上是不清楚的。雄激素，类固醇激素，循环在较高的水平， 男性比女性更有吸引力雄激素在躯体疼痛中具有抗伤害性， 有证据表明它们对内脏疼痛有类似的作用。在肠易激综合征（IBS）中， 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有明显的联系。 与其他类固醇一样，雄激素在肝脏中通过葡萄糖醛酸化失活并排泄到胆汁中。肠道中 在管腔中，这些非活性形式成为微生物β-葡萄糖醛酸苷酶（GUS）的底物， 葡萄糖醛酸苷部分，再生活性雄激素的大池。因此，雄激素再激活可能是一种 肠道微生物限制内脏高敏感性的关键机制，与先前的观察结果相关联。 这一建议的中心假设是，雄激素被微生物GUS信号直接激活到宿主 内脏传入神经元限制外周敏化和疼痛。首先，我们将建立独立的 肠道微生物、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。遗传学和 由co-I开发的微生物GUS酶的新型抑制剂， GUS化学，这一创新项目将PI的研究计划转移到内脏疼痛的新方向 和宿主-微生物相互作用。这项工作的影响将是推进对内脏的理解， 并为腹痛新的合理治疗靶点提供关键证据。