The Young Gut Microbiome: A Fountain of Youth for Brain Injury in the Aged?

年轻的肠道微生物组：老年人脑损伤的青春之泉？

• 批准号: 10806735
• 负责人: STEVEN J SCHWULST
• 金额: $ 221.64万
• 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: 2023-09-18 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10806735
• 关键词: Adopted; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anatomy; Attenuated; Automobile Driving; Biological Assay; Brain; Brain Injuries; CD8-Positive T-Lymphocytes; Candidate Disease Gene; Cause of Death; Cd68; Cell Separation; Cells; Cessation of life; Chronic; Clonal Expansion; Coculture Techniques; Complex; Coupled; Data; Dementia; Development; Feces; Flow Cytometry; Fluorine; Gene Expression Profile; Genotype; Histopathology; Human; Immune system; Incidence; Inflammatory Response; Injury; Intervention; Laboratories; Link; Macrophage Colony-Stimulating Factor Receptor; Magnetic Resonance Imaging; Measures; Metabolic; Microglia; Modeling; Molecular Profiling; Mus; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neuronal Plasticity; Outcome; Outcome Measure; PET/CT scan; Pathologic; Patients; Population; Process; Proliferating; Proteins; Publishing; RNA, Ribosomal, 16S; Risk Factors; Structure; T cell receptor repertoire sequencing; T-Cell Activation; T-Lymphocyte; TBI Patients; Testing; Trauma; Traumatic Brain Injury; United States; Variant; X-Ray Computed Tomography; Youth; age related; aged; aging brain; antigen-specific T cells; apolipoprotein E-4; behavioral phenotyping; biomarker development; cell age; cytokine; disability; experimental study; fecal transplantation; genetic risk factor; genetic variant; glial activation; gut microbiome; gut microbiota; improved; inhibitor; insight; metabolomics; microbial; molecular shape; nervous system disorder; neurogenesis; neuroinflammation; neuropathology; non-genetic; normal aging; novel; novel therapeutics; prebiotics; rRNA Genes; radiotracer; recruit; restoration; single-cell RNA sequencing; therapeutic development; transcriptome sequencing; transcriptomics; translational potential

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Patients aged 65 years and older account for an increasing proportion of patients with TBI and less than half of aged TBI patients become functionally independent after injury. In fact, TBI is one of the greatest non-genetic risk factors for the subsequent development of Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (ADRD). Chronic neuroinflammation resulting from the constitutive activation of microglia is complicit in AD, ADRD and related disease processes, and represents a complex interplay between aged microglia and the structure and function of the aged gut microbiome. However, the mechanism(s) underlying gut microbiota-microglia interaction in AD, ADRD, and aging have yet to be elucidated. Published Data from our laboratory shows that aged microglia adopt a constitutively activated state. These “primed” microglia are then capable producing an exaggerated inflammatory response and may represent one of the mechanisms leading to the increased incidence of Alzheimer’s disease and Alzheimer’s disease-related dementia in aged patients after TBI. Published and Preliminary Data from our laboratory further demonstrates that post-injury gut microbial community structure is a contributing factor in the degree of neurocognitive impairment including in AD and ADRD diagnoses after TBI. Our data shows that restoration of a preinjury gut microbial community markedly improved neurocognitive including AD/ADRD-related outcomes and attenuated the constitutive activation of microglia after TBI in mice. We published similar findings within the gut microbial community associated with normal aging with an increase in the relative abundance of several microbial taxa strongly associated with AD and ADRD. Nonetheless, mechanism(s) linking alterations in the aged gut microbial community to the development of subsequent AD and ADRD have yet to be fully elucidated. We hypothesize that restoration of a youthful gut microbial community before or after TBI will attenuate the constitutive activation of microglia and improve neurocognitive and AD/ADRD-related outcomes in aged TBI mice. To test this hypothesis we will determine whether restoring a youthful gut microbial community structure via fecal microbiota transplant with stool from young mice will attenuate the activation of microglia in aged mice. We will utilize both a pre-injury “prebiotic” model as well as a post-injury treatment paradigm. 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, we 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 intervention after TBI. Collectively, the proposed studies will identify the key role of an aged gut microbiome 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 aged TBI, AD, and ADRD patients.

创伤性脑损伤 (TBI) 是全球死亡和残疾的主要原因。 65 岁及以上的患者在 TBI 患者中所占比例越来越大，只有不到一半的老年 TBI 患者在受伤后能够恢复功能。小胶质细胞的组成性激活导致的慢性神经炎症是阿尔茨海默病 (AD) 和阿尔茨海默病相关痴呆 (ADRD) 的后续发展的最大非遗传风险因素之一。 AD、ADRD 和相关疾病过程，代表了衰老的小胶质细胞与衰老肠道微生物组的结构和功能之间的复杂相互作用。然而，AD、ADRD 和衰老中肠道微生物群-小胶质细胞相互作用的机制尚未阐明。我们实验室已发表的数据表明，老化的小胶质细胞处于一种组成性激活状态，然后能够产生过度的炎症反应，并且可能是导致炎症发生率增加的机制之一。我们实验室发表的阿尔茨海默病和阿尔茨海默病相关痴呆症的初步数据进一步表明，损伤后肠道微生物群落结构是导致神经认知障碍程度的一个因素，包括 TBI 后 AD 和 ADRD 的诊断。我们的数据表明，损伤前肠道微生物群落的恢复显着改善了神经认知，包括 AD/ADRD 相关结果，并减弱了 TBI 后小胶质细胞的组成性激活我们在小鼠肠道微生物群落中发表了与正常衰老相关的类似发现，其中一些微生物类群的相对丰度增加与 AD 和 ADRD 密切相关。随后的 AD 和 ADRD 的发展尚未完全阐明，TBI 之前或之后年轻的肠道微生物群落的恢复将减弱小胶质细胞的组成性激活并改善神经认知和功能。为了测试这一假设，我们将确定通过年轻小鼠的粪便移植粪便微生物群来恢复年轻的肠道微生物群落结构是否会减弱老年小鼠小胶质细胞的激活。我们将使用小胶质细胞的批量细胞分选 (FACSorting)，然后进行单细胞 RNA 测序 (scRNAseq)。我们将通过粪便 16S rRNA 基因扩增子测序和粪便代谢物分析来比较候选基因与微生物活性，并与转录组和肠道微生物群落分析相协调，我们将利用一种新型的 18-kDa 易位蛋白 (TSPO) 的纵向 PET/CT 成像。我们小组开发的基于氟的放射性示踪剂，用于跟踪和比较肠道微生物干预之前、期间和之后小胶质细胞激活的发生、进展和程度总的来说，拟议的研究将确定老年肠道微生物组在 TBI 过程中小胶质细胞活化的发生和进展中的关键作用，从而提高老年 TBI、AD 和 ADRD 的新型治疗和生物标志物开发的潜力。 。 患者。