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：已有充分证据表明，长期使用和滥用阿片类药物会引起 HIV 患者的细菌易位和持续的免疫激活，鉴于持续微生物易位对宿主造成的总体痛苦影响，不断积累的临床观察结果显示，微生物易位与 HIV 疾病进展之间存在很强的相关性。健康方面，可以想象，预防/阻止微生物易位的疗法可以用作艾滋病毒/艾滋病的新型治疗干预措施，并且可能对阿片类药物使用者/滥用者的艾滋病毒患者特别有益。微生物群在维持肠道稳态和肠道屏障完整性方面发挥着重要作用，肠道微生物组成的破坏已被证明对许多疾病过程的发生具有重要影响，而微生物是正常菌群的一部分。健康的宿主会增加对更具毒性的生物体成分的敏感性，从而导致屏障破坏和微生物易位。迄今为止，人们对肠道菌群在相关潜在机制中的作用知之甚少。无论是阿片类药物滥用者还是艾滋病患者，这种知识的缺乏都会对健康产生重要的负面影响，因为肠道微生物易位导致免疫激活，从而导致艾滋病相关的病理学，并且可能导致手足口病。使用微生物群谱分析群落组成差异，与安慰剂动物相比，吗啡治疗导致肠道细菌微生物群落显着不同，此外，导致微生物失调的因素，例如细菌群落数量显着减少和减少。在吗啡治疗组中也观察到了细菌多样性。根据我们的初步数据，我们发现吗啡对肠道微生物群的调节及其毒力在吗啡和吗啡 + HIV 诱导的肠道屏障破坏中发挥着核心作用，这导致细菌易位增加。为了检验这一假设，我们将在目标 1 中确定吗啡治疗后和中的微生物群落（粪便和粘膜相关）的丰度和物种多样性。 HIV 感染的背景及其对肠道屏障破坏、全身微生物易位和免疫激活的贡献目标 2：确定吗啡治疗动物和 HIV 背景下粘膜相关微生物群落的毒力特征、克隆性和抗生素耐药性。 （肠致病性大肠杆菌）。目标 3：确定甲基纳曲酮和 TLR2 拮抗剂在吗啡 HIV 诱导的肠道调节中的治疗潜力。微生物群和细菌毒力。