Non-genetic inheritance: mechanisms of microbiome-mediated transgenerational change

非基因遗传：微生物介导的跨代变化机制

• 批准号: 10434899
• 负责人: NICHOLE A BRODERICK
• 金额: $ 35.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434899
• 关键词: Acute; Animal Model; Animals; Chronic; Chronic Disease; Clostridium difficile; Complex; Coupled; Development; Disease; Drosophila genus; Drosophila melanogaster; Event; Gene Expression; Generations; Genes; Genome; Germ-Free; Gnotobiotic; Goals; Health; High-Throughput Nucleotide Sequencing; Human; Infection; Life; Link; Mediating; Modeling; Molecular; Molecular Genetics; Organism; Physiological; Physiology; Production; Regulation; Research; Signal Pathway; Signal Transduction; System; Technology; Work; dysbiosis; early experience; epigenome; experimental study; fecal transplantation; fly; genetic approach; host microbiome; host microbiota; human disease; interest; metabolome; microbial; microbial community; microbiome; microbiota; non-genetic; success; therapeutic target; tool; transcriptome; transplantation therapy

Project Summary The dense microbial communities associated with animals, referred to as the microbiome, can have an important impact on both host development and physiology. Yet, we are only beginning to understand the mechanisms by which the microbiome promotes these important functions. There is great interest to define and understand how these associations, such as changes in composition, or dysbiosis, are linked to a number of diseases. Moreover, the ability to manipulate or restore the microbiome is being pursued as a therapeutic target. While the success of fecal transplant therapy for acute and chronic Clostridium difficile infections highlights their potential, the broader applicability of such therapies to other maladies remains unknown. Consequently, there is great need to understand the relationship between a host and its microbiome with regards to its regulation and molecular signaling mechanisms. I propose to utilize the fruit fly, Drosophila melanogaster, to investigate mechanisms that contribute to the establishment of normal host physiological conditions, a critical step in developing strategies for microbiome therapy. My project will focus on the timing and establishment of normal parameters of host physiology and development. Specifically, I will study in germ-free flies and flies that have experienced early-life events that disrupt the microbiome, the latter of which has been linked to chronic diseases in other animal models. The specific goals of this proposal are to: a) Explore the trans-generational impacts of the microbiota on D. melanogaster. b) Identify host and microbiota factors that promote normal host physiology. c) Develop strategies to restore normal animal physiology through manipulation of the microbiome. I will use high throughput sequencing technologies in the form of transcriptomes, metabolomes, and epigenomes to investigate gene expression and metabolite production across fly development and through generations, coupled with traditional genetic approaches to characterize identified targets. My experiments will focus on comparisons with germ-free, gnotobiotic, and conventionally-reared flies to characterize the effects of host association with the microbiome. I will also identify microbial signals that induce changes in the host and will experimentally manipulate both the host and microbial recognition and signaling systems that mediate these associations. Given the high conservation of developmental and homeostatic signaling pathways between files and humans, and that 75% of known human disease genes have a match in the D. melanogaster genome, I anticipate that this work will identify conserved mechanisms that regulate host-microbiome interactions in all animals, including humans.

项目摘要 与动物相关的密集微生物群落，称为微生物组，可以具有 对宿主发育和生理都有重要影响。然而，我们才刚刚开始 了解微生物组促进这些重要功能的机制。有 有很大的兴趣来定义和理解这些协会，如组成的变化，或 生态失调与许多疾病有关。此外，操纵或恢复 微生物组作为治疗靶点。虽然粪便移植疗法的成功 急性和慢性艰难梭菌感染突出了它们的潜力， 这种治疗其他疾病的方法仍然是未知的。因此，非常需要了解 宿主与其微生物组之间的关系， 信号机制。我建议利用果蝇，黑腹果蝇，来研究 这些机制有助于建立正常的宿主生理条件， 开发微生物组治疗策略的步骤。我的项目将集中在时间和 建立宿主生理和发育的正常参数。具体来说，我将在 无菌苍蝇和经历过破坏微生物组的早期生命事件的苍蝇，后者 在其他动物模型中，这些疾病与慢性疾病有关。具体目标是 建议是：a）探索微生物群对D. 黑腹菌B）鉴定促进正常宿主生理学的宿主和微生物群因子。c）、 制定策略，通过操纵动物的 微生物组我将使用转录组形式的高通量测序技术， 代谢组和表观基因组，以研究果蝇的基因表达和代谢产物产生 发展和通过几代人，加上传统的遗传方法来表征 确定的目标。我的实验将集中在与无菌，无菌， 常规饲养的苍蝇来表征宿主与微生物组的关联的影响。我会 还可以识别诱导宿主变化的微生物信号，并将在实验上操纵这两种信号。 宿主和微生物的识别和信号系统介导这些关联。鉴于 高度保守的文件和人类之间的发展和稳态信号通路， 75%的已知人类疾病基因在D.黑腹果蝇基因组I 预计这项工作将确定调节宿主微生物组的保守机制， 在所有动物中的相互作用，包括人类。

项目成果

Microbiome-derived acidity protects against microbial invasion in Drosophila.

微生物组衍生的酸度可以保护果蝇免受微生物入侵。

• DOI: 10.1016/j.celrep.2024.114087
• 发表时间: 2024
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Barron,AlexanderJ;Agrawal,Sneha;Lesperance,DanielleNA;Doucette,Jeremy;Calle,Sthefany;Broderick,NicholeA
• 通讯作者: Broderick,NicholeA

Glyphosate inhibits melanization and increases susceptibility to infection in insects.

草甘膦抑制黑化并增加昆虫感染的易感性。

• DOI: 10.1371/journal.pbio.3001182
• 发表时间: 2021-05
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Smith DFQ;Camacho E;Thakur R;Barron AJ;Dong Y;Dimopoulos G;Broderick NA;Casadevall A
• 通讯作者: Casadevall A

Whole-genome sequences of two Drosophila melanogaster microbiome symbionts.

• DOI: 10.1128/mra.00602-23
• 发表时间: 2023-11-16
• 期刊: MICROBIOLOGY RESOURCE ANNOUNCEMENTS
• 影响因子: 0.8
• 作者: Barron, Alexander J.;Broderick, Nichole A.
• 通讯作者: Broderick, Nichole A.

Bacteria may be in the liver, but the jury is still out.

• DOI: 10.1172/jci158999
• 发表时间: 2022-04-15
• 期刊: The Journal of clinical investigation
• 作者: Broderick NA;Nagy L
• 通讯作者: Nagy L

Microbiome derived acidity protects against microbial invasion in Drosophila.

微生物组衍生的酸度可以保护果蝇免受微生物入侵。

• DOI: 10.1101/2023.01.12.523836
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Barron,AlexanderJ;Lesperance,DanielleNA;Doucette,Jeremy;Calle,Sthefany;Broderick,NicholeA
• 通讯作者: Broderick,NicholeA