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.

项目概要/摘要每年约有 300 万美国人遭受创伤性脑损伤 (TBI)。最高的 TBI 发生在 75 岁及以上的成年人中，他们的死亡率更高，长期生存状况更差。长期功能结果优于年轻人。这种与年龄相关的结果差异也在各种动物研究中都有报道。然而，分子和细胞机制仅尚未得到部分阐明，并且明显缺乏针对年龄的 TBI 治疗。我们发表的微生物组分析（16S RNA 基因测序）数据显示，老年小鼠 TBI 后证明有益共生肠道细菌的损失更大，机会性细菌的增加更多与年轻成年 TBI 小鼠相比，有害物种。肠道菌群失调的增加与老年 TBI 小鼠更严重的神经退行性变和神经认知缺陷相关。值得注意的是初步数据显示撞击损伤的大小显着减小并且衰减通过粪便将健康的微生物组转移到年轻的成年 TBI 小鼠中来治疗神经认知缺陷微生物组移植 (FMT) 因此，Davis 博士假设 TBI 后的植入将年轻的微生物组移植到老年小鼠体内将减轻神经退行性变和神经认知功能赤字。对于拟议研究的 K99 阶段，戴维斯博士将通过单一方法验证研究结果细胞 RNA 测序 (scRNA-seq) 用于询问小胶质细胞的转录谱 TBI 后经 FMT 治疗的老年小鼠的损伤过程。他还将比较微生物组 scRNA-seq 通过定量 MRI 进行解剖、神经认知和病理结果测量的数据，行为表型和组织病理学。对于拟议研究的 R00 阶段，博士。 Davis 将利用用 SCFA-重组的老年（80 周龄）无菌 (GF) C57BL/6 小鼠在 TBI 或假伤之前产生细菌溶纤维丁弧菌 (B. fib)。突变B.fib 产生少 10 倍的 SCFA 将用作对照。一组单独的老年野生型 C57BL/6 小鼠将接受含有 SCFA（丁酸盐、乙酸盐和丙酸盐）的水，而不是载体 TBI 后。 scRNAseq 将用于确定是否有针对性的微生物替代或 SCFA 饮食补充剂可以减弱小胶质细胞的激活。解剖学、神经认知和病理学结果测量将通过 MRI、行为表型分析和组织病理学来确定。总之，该提案将通过提供新的见解来填补当前老年 TBI 研究的空白。导致与衰老相关的不同 TBI 结果的分子和细胞机制，反过来，这可以查明潜在的衰老特异性 TBI 治疗靶点，这些靶点严重影响缺乏。