Fecal Microbiota Transfer Attenuates Aged Gut Dysbiosis and Functional Deficits after Traumatic Brain Injury

粪便微生物群转移可减轻老年肠道菌群失调和脑外伤后的功能缺陷

• 批准号: 10573109
• 负责人: Booker T Davis IV
• 金额: $ 11.82万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573109
• 关键词: Acetates; Address; Adult; Advisory Committees; Age; Aging; American; Anaerobic Bacteria; Anatomy; Animal Model; Animals; Attenuated; Award; Bacteria; Biology; Brain; Brain Injuries; Butyrates; Butyrivibrio; C57BL/6 Mouse; Cell Separation; Chronic; Clinical Trials; Complex; Data; Dietary Fatty Acid; Dietary Fiber; Dietary Intervention; Dietary Supplementation; Dimensions; Disease; Elderly; Fermentation; Flow Cytometry; Gene Expression Profile; Genes; Germ-Free; Goals; Grant; Histopathology; Immune; Immunology; Incidence; Injury; Intervention; Laboratories; Learning; Lesion; Magnetic Resonance Imaging; Mentors; Microglia; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Outcome; Outcome Measure; Pathologic; Phase; Population; Process; Propionates; Publishing; RNA; RNA, Ribosomal, 16S; Replacement Therapy; Reporting; Reproducibility; Research; Role; Shapes; Structure; Symptoms; TBI Patients; TBI treatment; Techniques; Training; Translating; Traumatic Brain Injury; Universities; Volatile Fatty Acids; Water; Work; aged; aging brain; attenuation; behavioral phenotyping; brain cell; career; clinical application; cohort; controlled cortical impact; dietary; expectation; fatty acid supplementation; fecal microbiota; fecal transplantation; functional outcomes; glial activation; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; gut-brain axis; improved; insight; knowledge base; meetings; metabolomics; microbial; microbiome; microbiome analysis; microbiota; minority scientist; mortality; mouse model; mutant; neuroinflammation; next generation; normal aging; novel; rRNA Genes; reconstitution; response; single-cell RNA sequencing; skill acquisition; skills; therapeutic target; translational potential; young adult

Project Summary/Abstract Traumatic brain injury (TBI) afflicts about three million Americans every year. The highest incidence of TBI occurs in adults aged 75 and older who have higher mortality and worse long- term functional outcomes than younger adults. This age-associated outcome difference has also been reported in various animal studies. Yet, the molecular and cellular mechanisms have only been partially elucidated, and age specific TBI treatments are notably lacking. Our published microbiome analysis (16S RNA gene sequencing) data revealed that aged mice post-TBI demonstrate a greater loss of beneficial commensal gut bacteria and a higher rise in opportunistic deleterious species in the compared to young adult TBI mice. This increase in gut dysbiosis correlated with worse neurodegeneration and neurocognitive deficits in aged TBI mice. Of note preliminary data reveals a significant decrease in the size of the impact lesion and an attenuation of neurocognitive deficits with transfer of a healthy microbiome into young adult TBI mice via fecal microbiome transplantations (FMT) Hence, Dr. Davis hypothesizes that the post-TBI placement of a young microbiome into an aged mouse will attenuate neurodegeneration and neurocognitive deficits. For the K99 phase of the proposed research, Dr. Davis will validate the findings via single cell RNA sequencing (scRNA-seq) to interrogate the transcriptional profiles of microglia over the course of injury in aged mice FMT treated post-TBI. He will also compare microbiome scRNA-seq data to anatomic, neurocognitive, and pathologic outcome measures with quantitative MRI, behavioral phenotyping, and histopathology. For the R00 phase of the proposed research, Dr. Davis will utilize aged (80-weeks-old) germ-free (GF) C57BL/6 mice reconstituted with the SCFA- producing bacterium Butyrivibrio fibrosolvens (B. fib) before TBI or sham injury. Mutant B.fib that produces 10-fold less SCFA will be used as a control. A separate cohort of aged wild type C57BL/6 mice will receive water containing SCFAs (butyrate, acetate, and propionate) vs. vehicle after TBI. scRNAseq will be used to determine if targeted microbial replacement or SCFA dietary supplementation can attenuate microglia activation. Anatomic, neurocognitive, and pathologic outcome measures will be determined with MRI, behavioral phenotyping, and histopathology. Together, this proposal will fill current gaps in geriatric TBI research by providing new insights into the molecular and cellular mechanisms leading to aging-associated differential TBI outcomes, which can, in turn, pinpoint potential aging-specific TBI therapeutic targets, which are severely lacking.

项目总结/摘要 创伤性脑损伤（TBI）每年折磨着大约300万美国人。最高 TBI的发病率发生在75岁及以上的成年人中，他们的死亡率更高， 长期功能结果比年轻的成年人。这种与年龄相关的结果差异也 在各种动物研究中也有报道。然而，分子和细胞机制只有 部分阐明，年龄特异性TBI治疗显着缺乏。我们的出版 微生物组分析（16 S RNA基因测序）数据显示，TBI后的老年小鼠 证明了有益的肠道细菌的更大损失和机会主义的更高上升， 与年轻的成年TBI小鼠相比，这种肠道生态失调的增加 与老年TBI小鼠中更严重的神经变性和神经认知缺陷相关。值得注意的 初步数据显示撞击损伤的大小显著减小， 通过粪便将健康的微生物组转移到年轻的成年TBI小鼠中， 微生物组移植（FMT）因此，戴维斯博士假设TBI后的放置 年轻的微生物组进入老年小鼠将减弱神经变性和神经认知 赤字对于拟议研究的K99阶段，戴维斯博士将通过单一的 细胞RNA测序（scRNA-seq），以询问小胶质细胞的转录谱， TBI后FMT治疗的老年小鼠的损伤过程。他还将比较微生物组scRNA-seq 定量MRI的解剖、神经认知和病理结果测量数据， 行为表型和组织病理学。对于R 00阶段的拟议研究，博士。 Davis将使用用SCFA-1000重组的老龄（80周龄）无菌（GF）C57 BL/6小鼠。 产生菌溶纤维丁酸弧菌（B.在TBI或假损伤之前。变种人B.撒谎说 产生少10倍的SCFA将用作对照。另一组老年野生型 C57 BL/6小鼠将接受含有SCFA（丁酸盐、乙酸盐和丙酸盐）的水与溶剂 脑外伤后。scRNAseq将用于确定靶向微生物替代或SCFA饮食 补充可减弱小胶质细胞活化。解剖、神经认知和病理 结果测量将通过MRI、行为表型和组织病理学来确定。 总之，这项提案将填补目前在老年TBI研究的空白，提供新的见解， 导致与年龄相关的不同TBI结果的分子和细胞机制， 反过来，它可以精确定位潜在的衰老特异性TBI治疗靶点，这些靶点严重 缺乏