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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要每年大约300万美国人遭受创伤性脑损伤（TBI）。最高 TBI发生的发生率发生在75岁及以上的成年人死亡率较高，长期较差的成年人发生率与年轻人相比，学期功能结果。这种与年龄相关的结果差异也有在各种动物研究中报道。然而，分子和细胞机制仅具有被部分阐明，并且特别缺乏特定年龄的TBI治疗。我们出版了微生物组分析（16S RNA基因测序）数据表明，TBI后老年小鼠证明有益的共生肠道细菌的损失更大，机会主义的上升更高与年轻的成年TBI小鼠相比，该物种有害物种。肠道营养不良的增加与老年TBI小鼠的神经退行性变化和神经认知缺陷相关。值得注意初步数据揭示了撞击病变的大小和衰减的大幅下降通过粪便将健康微生物组转移到年轻成年TBI小鼠中，神经认知缺陷的缺陷因此，微生物组移植（FMT）因此，戴维斯博士假设TBI位置年轻的微生物组成老鼠的小鼠会减弱神经变性和神经认知缺陷。对于拟议研究的K99阶段，戴维斯博士将通过单一验证发现细胞RNA测序（SCRNA-SEQ），以询问小胶质细胞的转录曲线老年小鼠FMT治疗后TBI的损伤过程。他还将比较微生物组scrna-seq 通过定量MRI进行解剖学，神经认知和病理结局指标的数据行为表型和组织病理学。对于拟议研究的R00阶段，博士戴维斯将利用与SCFA-重构的年龄（80周龄）无菌（GF）C57BL/6小鼠在TBI或假损伤之前产生细菌丁乙烯基纤维纤维溶胶（B. fib）。突变b.fib 生产少10倍SCFA将用作对照。单独的老年野生类型 C57BL/6小鼠将接收含有SCFA的水（丁酸酯，乙酸和丙酸杆菌）与车辆在TBI之后。 SCRNASEQ将用于确定靶向微生物置换还是SCFA饮食补充可以减弱小胶质细胞的激活。解剖学，神经认知和病理结果指标将通过MRI，行为表型和组织病理学确定。该提案一起将通过提供新的见解来填补老年TBI研究的当前空白导致与衰老相关的差异TBI结局的分子和细胞机制，反过来，它可以确定潜在的特异性TBI治疗靶标，这是严重的缺乏。