Investigating microbiota of the gut-brain axis and the impact of cocaine

研究肠脑轴的微生物群和可卡因的影响

• 批准号: 10625082
• 负责人: Gulnaz Javan
• 金额: $ 12.34万
• 依托单位: ALABAMA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625082
• 关键词: Actinobacteria class; Addictive Behavior; Adrenal Glands; Adverse effects; Affect; African; African American; African American population; Age; Alabama; American; Analysis of Variance; Autopsy; Bacteria; Bacteroidetes; Basal Ganglia; Bioinformatics; Biological Markers; Blood - brain barrier anatomy; Body mass index; Brain; Cadaver; Caring; Cells; Cerebrum; Cessation of life; Characteristics; Chloroform; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Colon; Communication; Data; Death Rate; Determination of Death; Development; Disease; Disparity; Distal; Double-Blind Method; Drug Addiction; Educational workshop; Endocrine system; Ensure; Evaluation; Farm; Fentanyl; Firmicutes; Florida; Future; Goals; Grant; Health; Homeostasis; Human; Hypothalamic structure; Illicit Drugs; Individual; Intoxication; Investigation; Knowledge; Leaky Gut; Link; Location; Mediating; Medical; Metagenomics; Microbe; Mood Disorders; Organ; Overdose; Pathogenesis; Personal Satisfaction; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenols; Pilot Projects; Pituitary Gland; Play; Polymerase Chain Reaction; Population; Predisposition; Process; Productivity; Proliferating; Proteobacteria; Race; Reproducibility; Research Personnel; Risk; Risk Factors; Role; Sampling; Science; Single-Blind Study; Site; Specimen; Sterility; Substance Use Disorder; Systems Analysis; Tennessee; Testing; Texas; Tissue Extracts; Tissues; Transverse colon; United States; Universities; Work; addiction; career; cocaine overdose; cocaine use; cost; drug of abuse; emotional behavior; experience; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; gut-brain axis; human tissue; ileum; innovation; insight; knowledgebase; mathematical model; metabolomics; microbial; microbial composition; microbial signature; microbiome; microbiota; microbiota-gut-brain axis; microorganism; mortality; novel; novel diagnostics; prevent; receptor binding; sex; therapeutic target; undergraduate student; virtual

PROJECT SUMMARY / ABSTRACT Cocaine abuse continues to be a national crisis, with the cost of addiction to illegal drugs in the United States related to criminal activity, lost work productivity, and medical care totaling more than $740 billion per year. In particular, African-Americans, who make up 13.4% of the U.S. population, disproportionately bear the burden of cocaine use and overdoses. Multiple studies have shown that prolonged use of cocaine affects the gut microbiota, which in turn alters hypothalamus-pituitary-axis activity and emotional behavior. Cocaine-related studies have shown that drugs of abuse trigger preferential proliferation of gram-positive Firmicutes and reduction of gram- negative Bacteroidetes, results that are consistent with microbiota associations with drug addiction. Accumulating evidence also shows that gut microorganisms influence the bidirectional communication along the gut- brain axis, which indicates the crucial role of the gut microbiota on cocaine. Since evidence exists for the influence of commonly abused drugs on the microbiota gut-brain axis, the transverse colon, the distal ileum, the basal ganglia, and the pituitary and adrenal glands may have potential roles as biomarkers, specifically in overdose cases, due to the damage to these tissues caused by cocaine abuse. In this proposal, we will address the impact that cocaine has on the microbiota of the gut-brain axis. Our approach will allow for evaluation of microbial signatures in microbiota gut-brain axis-associated tissues using specimens extracted from cocaine overdose cadavers, an approach that previous studies have not used but could provide information that helps determine how people respond differently to cocaine, allowing researchers to better examine the potential adverse effects of microbes. Specifically, we will test the hypothesis that there is a significant association between gut microbiota and the gut-brain axis in cocaine overdose cases from three Southern regions - Alabama, Florida, and Tennessee. To test this hypothesis, we will (1) determine whether the gut microbiome that is associated with the transverse colon and distal ileum mediates the relationship between cocaine use and lethal drug intoxication in African Americans from Southern regions of the United States; (2) determine whether the gut microbiome that is associated with the basal ganglia and the pituitary and adrenal glands mediates the relationship between cocaine use and lethal drug intoxication in African Americans from Southern regions of the United States;; and (3) validate a mathematical model of specific microbial biomarkers in single-blind studies using African-American tissues to increase confidence and demonstrate reproducibility. These processes will be evaluated and validated to provide a basis for new diagnostics as well as therapeutic targets to prevent intentional and unintentional cocaine overdose with the long-term objective of restoring gut microbiome homeostasis. In addition, the hands-on experience that the undergraduate students gain conducting phenol-chloroform extractions, polymerase chain reaction, and the workshop at the Freeman Ranch Body Farm at Texas State University in this project will provide them with insights into whether an academic career in biomedical sciences might be an avenue they want to further pursue.

项目概要/摘要 可卡因滥用仍然是一场全国性危机，美国非法毒品成瘾的代价高昂 与犯罪活动、工作效率损失和医疗保健相关的损失每年总计超过 7,400 亿美元。在 尤其是占美国人口 13.4% 的非洲裔美国人，承担着不成比例的负担。 可卡因的使用和过量。多项研究表明，长期使用可卡因会影响肠道微生物群， 这反过来又改变下丘脑-垂体轴活动和情绪行为。可卡因相关研究 研究表明，滥用药物会引发革兰氏阳性厚壁菌门的优先增殖和革兰氏阳性厚壁菌门的减少。 拟杆菌属阴性，结果与微生物群与药物成瘾的关联一致。积累中 证据还表明，肠道微生物影响肠道内的双向通讯。 脑轴，表明肠道微生物群对可卡因的关键作用。由于存在影响的证据 常见滥用药物对微生物群肠脑轴、横结肠、回肠远端、基底细胞的影响 神经节、垂体和肾上腺可能具有作为生物标志物的潜在作用，特别是在 由于滥用可卡因对这些组织造成损害而导致过量用药。在本提案中，我们将解决 可卡因对肠脑轴微生物群的影响。我们的方法将允许评估 使用从可卡因中提取的样本研究微生物群肠脑轴相关组织中的微生物特征 过量服用尸体，以前的研究尚未使用过这种方法，但可以提供有助于帮助的信息 确定人们对可卡因的不同反应，使研究人员能够更好地研究其潜力 微生物的不利影响。具体来说，我们将检验存在显着关联的假设 来自三个南部地区（阿拉巴马州）的可卡因过量病例中肠道微生物群与肠脑轴之间的关系 佛罗里达州和田纳西州。为了检验这一假设，我们将 (1) 确定肠道微生物组是否 与横结肠和远端回肠相关的可卡因使用和致死率之间的关系 来自美国南部地区的非裔美国人药物中毒； (2)判断是否肠道 与基底神经节、垂体和肾上腺相关的微生物组介导 来自南部地区的非裔美国人可卡因使用与致命药物中毒之间的关系 美国;; (3) 在单盲研究中验证特定微生物生物标志物的数学模型 使用非裔美国人的组织来增加信心并证明可重复性。这些过程将 进行评估和验证，为新的诊断和治疗目标提供基础，以防止故意 以及无意过量服用可卡因，其长期目标是恢复肠道微生物组稳态。在 此外，本科生获得的苯酚-氯仿的实践经验 提取、聚合酶链式反应以及德克萨斯州弗里曼牧场人体农场的研讨会 该项目中的大学将为他们提供有关生物医学科学学术职业是否可行的见解 可能是他们想要进一步追求的途径。