Unraveling gut-microbiome-brain interactions in neurodevelopmental disorders

揭示神经发育障碍中肠道-微生物-大脑的相互作用

• 批准号: 10390737
• 负责人: Mauro Costa-Mattioli
• 金额: $ 71.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390737
• 关键词: Animals; Area; Behavior; Behavioral; Bilateral; Brain; Brain region; Candidate Disease Gene; Central Nervous System Diseases; Complex; DNA Sequence Alteration; Data; Development; Dimensions; Disease; Dissection; Electrophysiology (science); Engineering; Environmental Risk Factor; Etiology; Exhibits; FMR1; Fiber; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Impairment; Individual; Laboratories; Lactobacillus reuteri; Lead; Mediating; Metagenomics; Microbial Genetics; Microbiology; Modeling; Molecular; Molecular Genetics; Mus; Neurodevelopmental Disorder; Neurons; Neurosciences; Oxytocin; Pathway interactions; Pharmacology; Physiology; Prevalence; Probiotics; Reproducibility; Research; Rewards; Role; Series; Signal Pathway; Signal Transduction; Social Behavior; Structure; Synaptic plasticity; System; Testing; Therapeutic; Vagotomy; Vagus nerve structure; Work; bacterial genetics; base; commensal bacteria; genetic makeup; gut microbes; gut microbiome; gut microbiota; gut-brain axis; improved; insight; loss of function; maternal obesity; metabolomics; microbial; microbiome alteration; microorganism; mouse model; multidisciplinary; novel; offspring; optogenetics; prevent; social; social deficits; synaptic function; tetrahydrobiopterin; transcriptome sequencing; transcriptomics

PROJECT ABSTRACT Most of the current focus in neurodevelopmental disorders (NDDs) research has been based on identifying key brain regions, relevant signaling pathways and selective brain circuits that give rise to overt behavioral and internal neuronal states Interestingly, we have recently found that that specific gut microbes can modulate brain function and behaviors in an amazingly powerful way via the gut-brain axis. Here we will combine state-of-the- art transcriptomics, metabolomics, pharmacology, microbiology, genetics, metagenomics, electrophysiology and behavior to identify the mechanism(s) by which a gut microbe (L. reuteri) reverses the social deficits in NDD mouse models. Briefly, we will define the molecular and genetic mechanism by which L. reuteri and L. reuteri- induced metabolites promote social behavior and related changes in synaptic function. In addition, we will identify the mode of gut-brain communication (‘gut-brain axis’) by which L. reuteri and L. reuteri-induced metabolites modulate brain function and behavior. Finally, we will assess the broader therapeutic potential for L. reuteri- induced metabolites in different models for NDDs with social dysfunction. Our findings could not only provide a new holistic dimension of how behaviors and the brain are controlled by gut microbes, but they could also lead to the development of new non-invasive microbial-based therapies for NDDs.

项目摘要 目前神经发育障碍（NDD）研究的大多数焦点都是基于识别关键的神经发育障碍。 大脑区域，相关的信号通路和选择性的大脑回路，引起明显的行为和 内部神经元状态有趣的是，我们最近发现特定的肠道微生物可以调节大脑 功能和行为通过肠道-大脑轴以一种惊人的强大的方式。在这里，我们将联合收割机的状态- art转录组学、代谢组学、药理学、微生物学、遗传学、宏基因组学、电生理学和 行为，以确定肠道微生物（L. reuteri）扭转了NDD的社会赤字 小鼠模型。简单地说，我们将定义的分子和遗传机制，L。reuteri和L.罗伊，罗伊 诱导的代谢物促进社会行为和突触功能的相关变化。此外，我们将确定 肠-脑交流模式（“肠-脑轴”），L. reuteri和L.罗伊特诱导代谢物 调节大脑功能和行为。最后，我们将评估L.罗伊，罗伊 诱导代谢物在不同的模型中的NDD与社会功能障碍。我们的发现不仅可以提供一个 行为和大脑如何由肠道微生物控制的新的整体维度，但它们也可能导致 致力于开发针对NDD的新型非侵入性微生物疗法。