Trauma, the gut, and the brain: the gut microbiota-microglia axis in traumatic brain injury

创伤、肠道和大脑：创伤性脑损伤中的肠道微生物群-小胶质细胞轴

• 批准号: 10673030
• 负责人: STEVEN J SCHWULST
• 金额: $ 61.01万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673030
• 关键词: Acetates; Alleles; Alzheimer' s Disease; American; Anaerobic Bacteria; Anatomy; Attenuated; Bacteria; Biota; Brain; Brain Injuries; Butyrates; C57BL/6 Mouse; Candidate Disease Gene; Cause of Death; Cell Separation; Cessation of life; Chronic; Clinical Trials; Clostridium; Cognitive; Communities; Complex; Data; Development; Dietary Fatty Acid; Dietary Fiber; Dietary Intervention; Dietary Supplementation; Disease; Feces; Fermentation; Fluorine; Gene Expression Profile; Generations; Genetic; Genotype; Germ-Free; Health Expenditures; Histopathology; Immune; Injury; Intervention; Laboratories; Lesion; Link; Magnetic Resonance Imaging; Measures; Metabolic; Microglia; Molecular Profiling; Morbidity - disease rate; Mus; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Outcome; Outcome Measure; PET/CT scan; Parkinson Disease; Pathologic; Population; Process; Propionates; Proteins; Publishing; RNA, Ribosomal, 16S; Shapes; Structure; Survivors; Symptoms; TBI Patients; Testing; Translating; Trauma; Traumatic Brain Injury; United States; Variant; Veins; Volatile Fatty Acids; X-Ray Computed Tomography; apolipoprotein E-4; behavioral phenotyping; biomarker development; brain cell; cohort; disability; drinking water; experimental study; fecal transplantation; genetic risk factor; genetic variant; glial activation; gut microbiome; gut microbiota; gut-brain axis; improved; metabolomics; microbial; microbiota; mortality; mouse model; nervous system disorder; neuroinflammation; novel; novel therapeutics; post stroke; rRNA Genes; radiotracer; reconstitution; response; single-cell RNA sequencing; therapeutic development; transcriptomics; translational potential; young adult

Project Summary/Abstract Trauma is the leading cause of death and disability in young adults in the United States. Traumatic brain Injury (TBI) contributes to over one third of all these trauma related deaths. In fact, TBI related healthcare expenditures near 80 billion dollars annually. The impact of TBI is highlighted not only by its high mortality rate, but also the significant long-term cognitive and psychiatric complications suffered by its survivors. Chronic neuroinflammation resulting from the constitutive activation of microglia is complicit in this process and represents a complex interplay between microglia and the gut microbiome via the gut-brain axis. However, the mechanism(s) underlying gut microbiota-microglia interaction have yet to be elucidated. Published Data from our laboratory shows a significantly altered gut microbial community after TBI, with increased relative abundance of several microbial species strongly associated with neurologic disease processes. In the same vein, it is known that reduced abundance of anaerobic bacteria capable of fermenting dietary fiber into short chain fatty acids (SCFAs) exacerbate lesion size and neuroinflammation after neurologic injury. Preliminary Data from our laboratory has shown improved neurocognitive outcomes with dietary supplementation of the SCFAs acetate, butyrate, and propionate after TBI. Nonetheless, the mechanism(s) linking TBI-induced alterations in the gut microbial community to the development of subsequent neurocognitive decline have yet to be fully elucidated. W hypothesize improve e that targeted microbial and dietary intervention will attenuate microglial activation and neurocognitive outcomes after TBI. To test this hypothesis,we will determine whether restoring a pre-injury gut microbial composition via fecal microbiota transplant, targeted microbiota replacement, or dietary supplementation of SCFAs attenuates the activation of microglia in wild type, germ-free, and genetic targeted replacement mice. We will use bulk population cell sorting (FACSorting) of microglia followed by single cell RNA sequencing (scRNAseq). We will compare candidate genes to microbial activity via fecal 16S rRNA gene amplicon sequencing and fecal metabolite analysis. Harmonized with the transcriptomic and gut microbial community profiling, all Aims will utilize longitudinal PET/CT imaging of the 18-kDa translocator protein (TSPO) with a novel fluorine-based radiotracer developed by our group to track and compare the onset, progression, and degree of microglial activation before, during, and after gut microbial and dietary intervention after TBI. Collectively, the proposed studies will identify the key role of gut microbial community structure and metabolic activity in the onset and progression of constitutive microglial activation over the course of TBI, thus raising the potential for novel therapeutic and biomarker development in TBI patients.

项目摘要/摘要 创伤是美国年轻人死亡和残疾的主要原因。创伤性脑损伤 在所有这些与创伤有关的死亡中，有三分之一以上是由创伤(TBI)造成的。事实上，与TBI相关的医疗支出 每年近800亿美元。脑外伤的影响不仅体现在其高死亡率上，而且还体现在 其幸存者长期遭受严重的认知和精神并发症。慢性神经炎 由小胶质细胞的结构性激活产生的产物在这一过程中是共谋的，代表着一种复合体 小胶质细胞和肠道微生物群之间通过肠道-脑轴相互作用。然而，机制(S) 肠道微生物区系与小胶质细胞之间的相互作用尚不清楚。我们实验室公布的数据 显示TBI后肠道微生物群落发生显著变化，相对丰度增加了几个 与神经系统疾病过程密切相关的微生物种类。同样，众所周知， 能够将膳食纤维发酵成短链脂肪酸(SCFAs)的厌氧菌数量减少 加重神经损伤后的损伤大小和神经炎症。我们实验室的初步数据显示 显示膳食补充单链脂肪酸醋酸酯、丁酸盐和 颅脑损伤后应用丙酸。尽管如此，脑损伤引起肠道微生物改变的机制(S) 社区对后续神经认知功能衰退的发展尚未完全阐明。W 假设 改进 E 有针对性的微生物和饮食干预将减弱小胶质细胞的激活和 颅脑损伤后的神经认知结果。为了检验这一假设，我们将确定是否恢复 通过粪便微生物区系移植、靶向微生物区系替代或饮食治疗的损伤前肠道微生物组成 补充单链脂肪酸可减弱野生型、无菌和遗传靶向小胶质细胞的激活 替换小鼠。我们将使用小胶质细胞的批量群体细胞分类(FACSorting)，然后是单细胞RNA 测序(ScRNAseq)。我们将通过粪便16S rRNA基因将候选基因与微生物活性进行比较 扩增片段测序和粪便代谢物分析。与转录和肠道微生物相协调 社区概况，所有AIMS将利用18-kDa转运蛋白(TSPO)的纵向PET/CT成像 使用我们团队开发的一种新型氟基放射性示踪剂来跟踪和比较患者的发病、进展和 以及伤后肠道微生物和饮食干预前、中、后小胶质细胞的活化程度。 总的来说，拟议的研究将确定肠道微生物群落结构和代谢的关键作用 在颅脑损伤过程中结构性小胶质细胞激活的开始和进展中的活性，从而提高了 脑外伤患者开发新的治疗和生物标记物的潜力。