Profiling the human gut microbiome for potential analgesic bacterial therapies

分析人类肠道微生物组以寻找潜在的镇痛细菌疗法

• 批准号: 10398329
• 负责人: Jack Anthony Gilbert
• 金额: $ 144.64万
• 依托单位: HOLOBIOME, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398329
• 关键词: Adjuvant Arthritis; Advanced Development; Alzheimer' s Disease; Anaerobic Bacteria; Analgesics; Animals; Anti Inflammatory Analgesics; Antibiotics; Antimicrobial Resistance; Autoimmune; Autoimmune Diseases; Bacteria; Bacterial Genes; Bacteriophages; Biological Assay; Biological Response Modifier Therapy; Biology; Blood; Blood Circulation; Cell Culture Techniques; Cells; Cellular Assay; Complex; Computational Biology; Culture-independent methods; Data; Development; Diclofenac; Diet; Dinoprostone; Disease; Distal; Dose; Ecology; Enzyme-Linked Immunosorbent Assay; Equilibrium; Etiology; Feces; Fibromyalgia; Freund' s Adjuvant; Future; Gastrointestinal tract structure; Generations; Genetic; Genetic Transcription; Genome; Genomics; Goals; Growth; Health; Heritability; Human; Human Biology; Immune; Immunoassay; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intervention Studies; Knock-out; Knowledge; Lactobacillus casei rhamnosus; Libraries; Link; Machine Learning; Malignant Neoplasms; Mammalian Cell; Maps; Measures; Metabolic; Metagenomics; Microbial Genetics; Microbiology; Modeling; Nature; Neurodegenerative Disorders; Neurotransmitters; Nociception; Oral; Outcome; Pain; Pain management; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Physiology; Preparation; Probiotics; Prostaglandin-Endoperoxide Synthase; Publishing; Rattus; Regulatory Pathway; Research; Resources; Rheumatoid Arthritis; Rodent; Role; Safety; Site; Source; Spinal Cord; Surveys; Symbiosis; TNF gene; TRP channel; Taxon; Taxonomy; Techniques; Testing; Therapeutic; Toxin; Validation; Weight-Bearing state; Work; antimicrobial; assay development; chronic pain; computerized tools; cytokine; design; dietary; experience; fecal transplantation; genome database; gut bacteria; gut microbes; gut microbiome; immunoregulation; in vitro Assay; in vivo; insight; laboratory equipment; lipidomics; macrophage; member; metabolomics; metagenomic sequencing; microbial; microbial genome; microbiome; microbiome composition; microbiome therapeutics; neurotransmission; non-opioid analgesic; novel; opioid epidemic; pain model; pain sensitivity; pathogen; programs; response; screening; small molecule; stem; therapeutic development; transcriptome sequencing; transcriptomics

The human gut microbiome is an essential component of host physiology: it modulates immune activity, influences the balance of neurotransmitters both peripherally and centrally, and produces a vast and variable array of small-molecule metabolites which enter circulation to impact distal body sites. It is highly heritable, implying a symbiosis that has developed over evolutionary timescales, but is also susceptible to the influence of diet and other factors such as antibiotic use. Notably, disruptions in microbiome composition are associated with a number of disorders characterized by chronic pain and inflammation, such as rheumatoid arthritis and fibromyalgia. Given the microbiome’s immunomodulatory and metabolic capacities, and its role as a pseudo- endogenous component of human biology, human gut-derived bacteria are a promising potential source of novel, safe, and non-addictive therapeutics for pain management. However, the mechanisms underlying the “gut–pain axis” are still being elucidated, and key functional drivers of the observed connections have yet to be identified. As such, to advance the development of microbiome-derived biotherapeutics for pain management, the goals of this project are: to identify human-gut-native bacteria capable of engaging established pain targets in vitro, to validate their activity and analgesic/anti-inflammatory potential in vivo, and to develop a computational tool to predict microbial-genetic drivers of response, which can guide future mechanism validation and therapeutic development. Because the vast majority of human gut bacteria are strictly anaerobic, they cannot be cultivated using typical laboratory equipment and techniques. This has historically presented a roadblock in mechanistic explorations of the gut microbiome’s therapeutic potential, resulting in a focus on “culture-independent” methods such as metagenomics—approaches that produce a wealth of correlative data, but little by way of causal validation. Holobiome is uniquely suited to meet this complex challenge, having overcome the difficulties inherent in anaerobic cultivation to build an in-house strain library of nearly ten thousand bacterial isolates from a variety of donors which contains representatives of nearly every major human gut-bacterial taxon cultured to date. This resource, along with an assembled team bringing extensive experience in microbiology, mammalian cell culture and assay development, and computational genomics, will allow a diverse library of human gut bacteria to be individually screened for their capacity to modulate cytokine response, cyclooxygenase expression, TRP channel activity, and other targets with high therapeutic potential for pain. This approach is expected to provide concrete insights on the mechanisms by which the gut microbiome influences nociception and the inflammatory response, with implications for the development of novel non-opioid analgesics. Findings of this research may also have translational potential for the treatment of autoimmune disorders, cancer, and neurodegenerative diseases such as Alzheimer’s Disease, which has both autoimmune components and demonstrated links to the microbiome.

人类肠道微生物组是宿主生理学的重要组成部分：它调节免疫活性， 影响周围和中枢神经递质的平衡，并产生巨大的和可变的 一系列小分子代谢物进入循环，影响身体远端部位。它是高度遗传的， 这意味着一种共生关系已经在进化的时间尺度上发展起来，但也容易受到 饮食和其他因素，如抗生素的使用。值得注意的是，微生物组组成的破坏与 许多以慢性疼痛和炎症为特征的疾病，如类风湿性关节炎和 纤维肌痛考虑到微生物组的免疫调节和代谢能力，以及其作为伪 作为人类生物学的内源性成分，人类肠道来源的细菌是一种有希望的潜在的新的， 安全、无成瘾性的疼痛治疗方法。然而，“肠痛”的潜在机制 “轴心”仍在阐明之中，所观察到的联系的关键功能驱动因素尚未确定。 因此，为了促进用于疼痛管理的微生物组衍生的生物治疗剂的开发， 该项目是：鉴定能够在体外参与既定疼痛靶点的人类肠道原生细菌， 在体内验证其活性和镇痛/抗炎潜力，并开发计算工具， 预测响应的微生物遗传驱动因素，这可以指导未来的机制验证和治疗 发展由于绝大多数人类肠道细菌是严格厌氧的，因此无法培养 使用典型的实验室设备和技术。这在历史上是机械化的障碍。 探索肠道微生物组的治疗潜力，导致关注“非培养”方法 例如宏基因组学--产生大量相关数据的方法，但很少通过因果关系 验证。Holobiome是唯一适合迎接这一复杂挑战，克服了固有的困难， 在厌氧培养中，建立了一个包含近万种细菌分离物的内部菌株库， 其中包含迄今为止培养的几乎所有主要人类肠道细菌分类群的代表。这 资源，沿着一个集合的团队，带来了在微生物学，哺乳动物细胞培养， 和分析开发，以及计算基因组学，将允许一个多样化的人类肠道细菌库， 分别筛选它们调节细胞因子应答、环氧合酶表达、TRP通道 活性和其他具有高疼痛治疗潜力的靶点。预计这一做法将提供具体的 了解肠道微生物组影响伤害感受和炎症反应的机制， 这对开发新型非阿片类镇痛药具有重要意义。这项研究的结果也可能 用于治疗自身免疫性疾病、癌症和神经退行性疾病， 阿尔茨海默氏病，既有自身免疫成分，又与微生物组有关。