Gut microbiota disruption by Morphine and in the context of HIV infection contributes to sustained immune activation

吗啡和 HIV 感染情况下肠道微生物群的破坏有助于持续的免疫激活

• 批准号: 9338221
• 负责人: Timothy J Johnson
• 金额: $ 57.23万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9338221
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Animals; Antibiotic Resistance; Attenuated; Bacterial Translocation; Bacteroidetes; Cardiovascular Diseases; Chronic; Clinical; Clonality; Communities; Comorbidity; Control Animal; Data; Development; Disease; Disease Progression; Drug Addiction; Drug abuse; Drug usage; Drug user; Epidemic; Equilibrium; Feces; HIV; HIV Infections; HIV-1; Health; Homeostasis; Infection; Inflammatory Bowel Diseases; Intestines; Investigation; Knowledge; Laboratories; Link; Malignant Neoplasms; Microbe; Modeling; Morbidity - disease rate; Morphine; Mucous Membrane; Mus; Naltrexone; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Opiates; Opioid; Organism; Osteoporosis; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Placebos; Play; Population; Predisposition; Process; Publishing; Reporting; Role; TLR2 gene; Testing; Therapeutic; Time; Treatment Efficacy; Virulence; Virulent; antiretroviral therapy; base; design; drug abuser; enteropathogenic Escherichia coli; epidemiology study; experimental study; gut microbiota; humanized mouse; illicit drug use; immune activation; microbial; microbial community; microbiota; microorganism; mortality; novel therapeutic intervention; opioid abuse; opioid use; prevent; public health relevance; statistics; therapeutic evaluation; trait

 DESCRIPTION: Chronic Opioid use and abuse has been well documented to induce bacterial translocation and sustained immune activation. In HIV patients, accumulating clinical observations show a strong correlation between microbial translocation and HIV disease progression. Given the overall detrimental effect of sustained microbial translocation on host health, it is conceivable that therapies to prevent/block microbial translocation can be exploited as novel therapeutic intervention in HIV/AIDS and may be particularly beneficial in HIV patients that are opioid users/abusers. The gut microbiota, play a significant role in maintaining gut homeostasis and gut barrier integrity. Disruption in the composition of intestinal microbes has been shown to have important implications in the development of a number of disease processes. Loss of microorganisms which are part of the normal flora of healthy hosts increases the susceptibility to a more virulent composition of organism that can contribute to barrier disruption and microbial translocation. Thus far, very little is known regarding the role of the gu microbiota in the underlying mechanisms involved in the increased microbial translocation in either opioid abusers or in HIV patients. This lack of knowledge has important negative health- related implications since gut microbial translocation leading to immune activation contributes to AIDS related pathology and possibly HAND. Our preliminary data show for the first time that when community composition dissimilarity was analyzed using microbiota profiles morphine treatment resulted in a significantly different cluster in gut bacterial microbial composition compared to placebo animals. Furthermore, factors that contribute to microbial dysbiosis such as significant decrease in the number of bacterial community and reduced bacterial diversity was also observed in the morphine treated group. Based on our preliminary data, we hypothesize that morphine modulation of the gut microbiota and its virulence play a central role in morphine and morphine +HIV induced intestinal barrier disruption. This results in increased bacterial translocation, immune activation and contributes to HIV disease progression. To test the hypothesis we will in Aim 1: Determine the abundance and species diversity of the microbiota community (stool and mucosa associated) following morphine treatment and in the context of HIV infection and its contribution to gut barrier disruption and systemic microbial translocation and immune activation. Aim 2: Determine the virulence traits, clonality, and antibiotic resistance of the mucosa-associated microbial community in morphine treated animals and in the context of HIV. (Enteropathogenic Escherichia coli). Aim 3: Determine the therapeutic potential of methyl naltrexone and TLR2 antagonists in morphine HIV induced modulation of gut microbiota and bacterial virulence.

 描述：慢性阿片类药物的使用和滥用已被充分记录在诱导细菌易位和持续的免疫激活。在HIV患者中，积累的临床观察结果表明，微生物易位与HIV疾病进展之间存在很强的相关性。鉴于持续微生物易位对宿主健康的总体有害作用，可以想象可以将预防/阻断微生物易位的疗法被用作艾滋病毒/艾滋病的新型治疗干预措施，并且在阿片类药物/虐待者的HIV患者中可能特别有益。肠道微生物群在保持肠道稳态和肠道屏障完整性方面起着重要作用。肠道微生物组成的破坏已被证明对许多疾病过程的发展具有重要意义。是健康宿主正常菌群的一部分的微生物的丧失增加了对生物体更具毒性成分的敏感性，这可能有助于屏障破坏和微生物易位。关于GU微生物群在阿片类药物滥用者或HIV患者中微生物易位增加的基本机制中所涉及的基本机制中的作用，知之甚少。由于肠道微生物易位导致免疫激活会导致与艾滋病相关的病理和可能的手，因此这种知识的缺乏具有重要的负面健康相关意义。我们的初步数据首次表明，与安慰剂动物相比，当使用微生物元素剖面分析社区组成差异时，吗啡处理导致肠道细菌微生物组成的簇显着不同。此外，在吗啡治疗组中还观察到了导致微生物营养不良的因素，例如细菌群落数量的显着减少和细菌多样性的减少。根据我们的初步数据，我们假设肠道菌群的吗啡调节及其病毒在吗啡和吗啡 +HIV诱导的肠道屏障破坏中起着核心作用。这导致细菌易位，免疫激活并导致HIV疾病进展。为了检验假设，我们将在目标1：确定吗啡治疗以及HIV感染及其贡献的目标2：确定病毒性状，克隆性和粘液相关的粘膜相关抗生素抗生素抗生素的抗粘液相关的动物治疗和抗性动物的抗生素抗性，确定菌群群落的抽象和物种多样性（粪便和粘膜相关）。 （肠病大肠杆菌）。 AIM 3：确定吗啡HIV诱导的肠道菌群和细菌病毒的调节中甲基纳曲酮和TLR2拮抗剂的治疗潜力。