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.

项目总结 腹痛是消化系统疾病的一种常见症状，现有的治疗方法很难解决这一问题。 益生菌被广泛用于治疗腹痛，尽管大多数研究都检验了它们的效果 都有令人失望的结果。一种更有效的策略可能是刺激特定的微生物途径 已经存在于肠道中，对宿主有利。这项提案的首要目标是确定一个 重新激活肠腔中类固醇的微生物途径通常调节感觉神经元的活动 它调节内脏感觉，以及这条通路是否可以被操纵来影响腹痛。 腹痛是由内脏传入调节的，内脏传入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，共生 微生物区系通常限制内脏传入敏感度。共生微生物的枯竭导致夸大 对结直肠扩张的反应，内脏传入对非伤害性过敏的证据 在没有微生物的情况下产生刺激。微生物对内脏疼痛的全面影响及其信号 然而，调解他们在很大程度上是不清楚的。雄激素，类固醇激素，在体内循环水平较高 男性多于女性，是有说服力的候选人。雄激素在躯体疼痛和新兴疾病中具有抗伤害性 有证据表明，它们对内脏疼痛也有类似的影响。在肠易激综合征(IBS)中，一种疾病 根据慢性腹痛的定义，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，雄激素动态平衡与肠道微生物区系有明显的联系。 和其他类固醇一样，雄激素在肝脏中被葡萄糖醛酸化作用灭活，并被排泄到胆汁中。在肠子里 腔，这些不活跃的形式成为微生物β-葡萄糖醛酸苷酶(GU)的底物，这种酶可以去除 葡萄糖醛酸苷部分，再生一大堆活跃的雄激素。因此，雄激素重新激活可能是一种 与之前的观察结果相联系，共生微生物限制内脏过敏的关键机制。 这一提议的中心假设是，由微生物GUS重新激活的雄激素直接向宿主发出信号 内脏传入神经元，以限制外周敏感和疼痛。首先，我们将建立独立的 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连接。结合了遗传和 灵知生菌小鼠模型以及由co-i开发的微生物GUS酶的新型抑制剂，该公司是 GUS化学，这个创新的项目将PI的研究项目推向内脏疼痛的新方向 以及宿主与微生物的相互作用。这项工作的影响将是促进对内脏的理解 并为腹痛新的合理治疗靶点提供关键证据。