Microbial reactivation of sex steroids and visceral pain

性类固醇的微生物再激活和内脏疼痛

基本信息

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
项目类别：
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

项目摘要

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.

项目概要腹痛是消化系统疾病的常见症状，现有疗法很难解决。尽管大多数研究都检验了益生菌的作用，但益生菌被广泛用于治疗腹痛一个更有效的策略可能是刺激微生物的特定途径。该提案的总体目标是确定是否已经存在于肠道中，从而使宿主受益。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介导内脏感觉，以及是否可以操纵该通路来影响腹痛。腹痛是由内脏传入神经介导的，内脏传入神经元位于肠道外，先前的研究表明，共生体将信息从肠道传递到中枢神经系统。微生物群通常会限制内脏传入敏感性。共生微生物的耗竭会导致过度敏感。对结直肠扩张的反应，证据表明内脏传入对非有害物质变得过敏在没有微生物的情况下，微生物对内脏疼痛的影响的全部程度以及信号。然而，雄激素（在体内水平较高时消除的类固醇激素）对它们的调节作用在很大程度上尚不清楚。男性比女性更引人注目，雄激素在躯体疼痛和新出现的疼痛中具有抗伤害作用。有证据表明它们对肠易激综合症（IBS）的内脏疼痛有类似的作用。以慢性腹痛为定义，我们发现低雄激素水平与诊断和治疗有关。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而失活并排泄到肠道中的胆汁中。在管腔中，这些非活性形式成为微生物 β-葡萄糖醛酸酶 (GUS) 的底物，从而去除葡萄糖醛酸苷部分，再生大量活性雄激素因此，雄激素重新激活可能是一个因素。共生微生物限制内脏过敏的关键机制，与之前的观察结果相联系。该提案的中心假设是微生物 GUS 信号重新激活的雄激素直接向宿主发出信号内脏传入神经元限制外周敏化和疼痛首先，我们将建立独立性。共生微生物、微生物 GUS 活性和内脏传入神经元雄激素信号传导的影响然后，我们将测试每个组成部分之间的机制联系。无菌小鼠模型以及由 co-I（该领域的领导者）开发的新型微生物 GUS 酶抑制剂 GUS 化学，这个创新项目将 PI 的研究项目推向内脏疼痛的新方向这项工作的影响将是促进对内脏的理解。感觉并为腹痛的新合理治疗目标提供关键证据。