Role of Gut Microbiome in HIV/Opioid Induced Peripheral Neuropathy

肠道微生物组在 HIV/阿片类药物引起的周围神经病变中的作用

• 批准号: 10163152
• 负责人: SHUANGLIN HAO
• 金额: $ 46.45万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163152
• 关键词: Absence of pain sensation; Analgesics; Anti-Retroviral Agents; Attenuated; Back; Bacterial Translocation; Beta-glucuronidase; Blood Circulation; Cells; Chronic; Complication; Data; Development; Dose; Enteral; Enzymes; Epithelial Cells; Exhibits; Exposure to; Functional disorder; Genetic Engineering; Glucuronides; Glucuronosyltransferase; HIV; HIV Infections; HIV Seropositivity; HIV neuropathy; HIV-1; Hyperalgesia; Immune; Infection; Interleukin-6; Knockout Mice; Knowledge; LoxP-flanked allele; Mammals; Metabolic Pathway; Microglia; Morphine; Morphine Derivatives Including Cocaine; Mus; Neurologic; Nociceptive Stimulus; Opioid; Opioid Analgesics; Opioid abuser; Pain; Pain management; Parents; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Population; Prevalence; Recycling; Reporting; Rodent; Role; Serum; Signal Transduction; Small Intestines; TLR2 gene; Testing; Therapeutic; Thermal Hyperalgesias; Tissues; Toxic effect; Zidovudine; bacterial community; base; commensal bacteria; cytokine; dysbiosis; gastrointestinal epithelium; gut microbiome; gut microbiota; inhibitor/antagonist; intestinal barrier; knock-down; mechanical allodynia; microbial; microbial community; morphine-3-glucuronide; morphine-6-glucuronide; non-drug; non-nucleoside reverse transcriptase inhibitors; opioid abuse; opioid use; opioid user; painful neuropathy; preservation; reconstitution

Project Summary Prolonged use opioids results in a paradoxical increase in atypical pain (hyperalgesia). Despite its known limitations, mechanisms underlying opioid-induced hyperalgesia still remains a significant gap in knowledge. Peripheral neuropathy has become the most common neurologic complication in HIV patients, with prevalence as high as 69.4% in infected patients, Notably, HIV-infected opioid abusers appear to exhibit more severe neuropathy than HIV-infected non-drug users. Furthermore, repeated use of opioid analgesics are reported to promote neuropathic pain in HIV patients. Very little is known if ART contributes to peripheral neuropathy and if it is exacerbated in chronic opioid users. The main metabolic pathway for morphine and morphine derivatives in mammals is glucuronidation catalyzed by UDP-glucuronosyltransferase (UGT) enzymes. Morphine is metabolized predominantly to two metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) (1,2). M-3-G is the only metabolite produced in rodents and does not have any analgesic effects but have been shown in recent studies to activate and modulate TLR signaling. Furthermore, antiretroviral drugs particularly, intergrase inhibitors, are also metabolized through the UGT- glucuronidation pathway. Recent studies show that the metabolites of the intergrase inhibitor zidovudine to be more toxic than the parent compound. In preliminary data we show that chronic morphine treatment results in significant gut microbial dysbiosis with significant decrease in bacterial communities that synthesize β-glucuronidase with a concurrent decrease in glucuronidase activity. We show in preliminary data that depletion in the bacterial communities involved in the synthesis of β -glucuronidase results in a) increased accumulation M-3-G in the gut and serum and b) reduced enterohepatic recycling of morphine. We further demonstrate that morphine treatment in the context of HIV infection results in significant hyperalgesia in the both the Mechanical allodynia (Von Frey) and Thermal hyperalgesia test (Hargraves) tests. Proinflammatory cytokine levels and morphine induced hyperalgesia are significantly attenuated in TLR2 knock out mice. Based on these observations we hypothesize that decreased microbial communities associated with β glucuronidase synthesis following prolonged exposure to high dose morphine results in accumulation of M-3-G morphine metabolite and toxic glucuronidated ART in the small intestine contributing to Specific Aim 1: Establish that accumulation of the morphine metabolite M-3-glucoronide in the gut results in opioid induced hyperalgesia and HIV induced peripheral neuropathy in opiod using HIV patients. Specific Aim 2: Determine the role of TLR2 signaling in morphine induced hyperalgesia and HIV associated peripheral neuropathy in the context of ART treatment. Specific Aim 3: Treatment with genetically engineered commensal bacteria with controlled expression of B- glucuronidase in combination with TLR2/4 antagonist will preserve small intestinal barrier integrity and attenuate peripheral neuropathy and prolong morphine analgesia.

项目摘要 长时间使用阿片类药物会导致非典型疼痛（Hypergerseia）的矛盾增加。尽管已知 局限性，阿片类药物诱导的痛觉过敏的机制仍然是知识的显着差距。 周围神经病已成为HIV患者中最常见的神经系统并发症，患病率 受感染患者的高达69.4％，尤其是感染HIV感染的阿片类药物滥用者似乎表现更严重 神经病比感染HIV的非药物用户。此外，据报道反复使用阿片类镇痛药 促进HIV患者的神经性疼痛。鲜为人知的艺术是否有助于周围神经病和 在慢性阿片类药物用户中会加剧。吗啡和吗啡衍生物的主要代谢途径 在哺乳动物中，是由UDP-葡萄糖基转移酶（UGT）酶催化的葡萄糖醛酸化。吗啡是 代谢主要为两种代谢物，吗啡-3-葡萄糖醛酸（M3G）和吗啡-6-葡萄糖苷剂 （M6G）（1,2）。 M-3-G是啮齿动物中唯一产生的代谢物，没有任何镇痛作用，但具有 在最近的研究中，我们被证明了激活和调节TLR信号传导。此外，抗逆转录病毒药物 特别是，跨抑制剂也通过UGT-葡萄糖醛酸糖苷化途径代谢。最近的 研究表明，晶间抑制剂齐多夫丁的代谢产物比父母更具毒性 化合物。在初步数据中，我们表明慢性吗啡治疗可导致明显的肠道微生物 营养不良，细菌群落显着降低，这些群落与并发合成β-葡萄糖醛酸酶合成 糖蛋白酶活性的降低。我们在细菌群落中部署的初步数据中显示 参与β-葡萄糖醛酸酶合成的合成导致a）肠内积累M-3-G的增加 b）降低吗啡的肠肝癌回收。我们进一步证明了吗啡治疗 HIV感染的背景会导致机械性异常（von Frey）和 热痛觉测试（HARGRAVES）测试。促炎细胞因子水平和吗啡诱导 在TLR2中，高温高温显着减弱。基于这些观察，我们假设 这改善了与β糖蛋白酶合成相关的微生物群落。 暴露于高剂量吗啡会导致M-3-G吗啡代谢物和有毒的积累 小肠中的谷氨酸化艺术有助于特定目的1：确定积累 肠道中的吗啡代谢产物M-3-葡萄糖醛酸酮导致阿片类药物诱导的痛觉过敏和HIV诱导 使用HIV患者在OPIOD中的周围神经病。特定目标2：确定TLR2信号在 吗啡在艺术治疗的背景下诱导的痛觉过敏和HIV相关的周围神经病。 特定的目标3：用一般设计的共生细菌治疗B- 葡萄糖醛酸酶与TLR2/4拮抗剂结合使用将保持小肠屏障完整性并减弱 周围神经病和延长吗啡镇痛。