Microbiome-derived small molecules and host resistance against Vibrio cholerae

微生物组衍生的小分子和宿主对霍乱弧菌的抵抗力

• 批准号: 10867140
• 负责人: Luis Caetano Martha Antunes
• 金额: $ 21.21万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10867140
• 关键词: Anti-Infective Agents; Bacteria; Biological Assay; Biology; Categories; Chemicals; Cholera; Collection; Communicable Diseases; Communication; Complex; Development; Environment; Feces; Food; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Health; Host resistance; Human; Human body; Immune system; Infection; Mass Spectrum Analysis; Microbe; Modeling; Nature; Nuclear Magnetic Resonance; Pathogenesis; Pathogenicity; Phenotype; Play; Property; Repression; Role; Salmonella enterica; Signal Transduction; Signaling Molecule; Source; Therapeutic; Vibrio cholerae; Virulence; Work; cell motility; fecal metabolome; gene repression; gut microbiota; human pathogen; insight; microbial community; microbiome; microbiota; microbiota metabolites; pathogen; response; small molecule; transcriptome; virulence gene

The human body is colonized by a complex microbial community with critical roles for health. This microbiota educates the immune system, helps digest our food, and protects us against pathogens. The diversity of microbes and encoded functions is significant. Our group showed that the gut microbiota is also a source of great chemical diversity, and that most of the compounds produced are unknown. Bacteria produce and respond to small molecules to communicate and adapt to their environment. Chemical signaling controls functions that are critical for host adaptation in most pathogens. Therefore, small-molecule signaling is an attractive target for the development of anti-infectives. Given the chemical complexity of the gut, microbiotapathogen crosstalk must be common. In fact, we previously showed that an organic extract of human feces elicits a significant transcriptional response in Salmonella enterica, with ~100 regulated genes. Interestingly, virulence genes were abundant among those repressed by the extract, suggesting that microbiota-derived metabolites can dampen virulence. We then determined that a single commensal, Enterocloster citroniae, can repress S. enterica virulence gene expression. More recently, we studied the transcriptional impact of the human fecal metabolome on other pathogens. In Vibrio cholerae, the causative agent of cholera, the effect was even more pronounced, with ~900 genes being regulated. Motility was the main category of repressed genes, and the effect was confirmed by phenotypic assays. As with S. enterica, the effect could be recapitulated with E. citroniae. Given the importance of V. cholerae as a human pathogen and the critical role played by motility in its pathogenesis, it is our goal to determine the impact of microbiota-derived metabolites on V. cholerae pathogenicity. We will generate a collection of gut commensals with anti-motility properties to characterize the genetic and chemical nature of the bioactivity. Genomes and transcriptomes of active and inactive strains will be compared, giving insights into the synthetic apparatus involved. Bioactivity-guided purification will be performed, and compound characterization using mass spectrometry and nuclear magnetic resonance will ensue. Lastly, we will study the impact of active strains and compounds on host resistance to V. cholerae using infection models. Results from this work will shed light on the chemical biology of microbiota-pathogen interactions and may reveal strains and compounds with potential therapeutic applications.

人体栖息着一个复杂的微生物群落，对健康起着至关重要的作用。这个微生物群 教育免疫系统，帮助消化我们的食物，并保护我们免受病原体的侵害。的多样性 微生物和编码功能具有重要意义。我们的小组表明，肠道微生物群也是 巨大的化学多样性，并且产生的大多数化合物都是未知的。细菌产生和 对小分子做出反应以进行交流并适应环境。化学信号控制 对大多数病原体的宿主适应至关重要的功能。因此，小分子信号传导是一种 抗感染药物开发的有吸引力的目标。鉴于肠道化学的复杂性，微生物病原体 串扰一定很常见。事实上，我们之前已经证明，人类粪便的有机提取物 在肠道沙门氏菌中引发显着的转录反应，约有 100 个受调控基因。有趣的是， 毒力基因在被提取物抑制的基因中含量丰富，这表明源自微生物群的毒力基因 代谢物可以减弱毒力。然后我们确定了一种共生菌，柠檬肠杆菌， 可以抑制肠沙门氏菌毒力基因的表达。最近，我们研究了转录影响 其他病原体的人类粪便代谢组。在霍乱的病原体霍乱弧菌中， 效果更加明显，约 900 个基因受到调节。动力性是主要类别 抑制基因，其效果通过表型测定得到证实。与肠沙门氏菌一样，其效果可能 可以用 E. citroniae 来概括。鉴于霍乱弧菌作为人类病原体的重要性以及关键 运动在其发病机制中发挥的作用，我们的目标是确定微生物群来源的影响 代谢物对霍乱弧菌致病性的影响。我们将生成一组具有抗蠕动性的肠道共生体 特性来表征生物活性的遗传和化学性质。基因组和转录组 将比较活性菌株和非活性菌株，从而深入了解所涉及的合成装置。 将进行生物活性引导的纯化，并使用质谱法进行化合物表征 核磁共振将会随之发生。最后，我们将研究活性菌株和化合物的影响 使用感染模型研究宿主对霍乱弧菌的抵抗力。这项工作的结果将揭示该化学物质 微生物群-病原体相互作用的生物学，并可能揭示具有潜在治疗作用的菌株和化合物 应用程序。