Exploring Akkermansia Genomic and Functional Diversity in Neurologic Diseases

探索神经系统疾病中阿克曼氏菌的基因组和功能多样性

• 批准号: 10431617
• 负责人: Laura Michelle Cox
• 金额: $ 47.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431617
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyotrophic Lateral Sclerosis; Astrocytes; Bacteria; Bacteroides; Biological; Brain; Collection; Data; Disease; Elements; Epilepsy; Exhibits; Experimental Autoimmune Encephalomyelitis; Gene Expression; Genes; Genetic Transcription; Genomics; Germ-Free; Growth; In Vitro; Inflammation; Interleukin-17; Intestinal Content; Investigation; Link; Metabolic; MicroRNAs; Microglia; Multiple Sclerosis; Mus; Neurodegenerative Disorders; Neurons; Niacinamide; Oligodendroglia; Output; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Production; Reporting; Resources; Role; Serum; Severity of illness; T-Lymphocyte; Testing; Therapeutic; Time; Toxin; Variant; Vitamin B 12; Vitamins; base; beneficial microorganism; brain tissue; cell type; experimental study; genome sequencing; gut bacteria; gut microbiota; gut-brain axis; insight; metabolomics; microbial; mouse model; multiple sclerosis patient; nervous system disorder; novel; novel therapeutic intervention; protective effect; protein degradation; superoxide dismutase 1; transcriptome sequencing; whole genome

The gut microbiota can influence neurologic diseases, including Alzheimer’s disease (AD), Parkinson’s disease dementia (PDD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and epilepsy. However, the role of specific bacteria and how they relate to disease-specific mechanisms in AD and AD-related dementias (ADRD) vs. non-dementia neurologic diseases is unexplored. Akkermansia muciniphila has emerged as a beneficial microbe with therapeutic potential for AD, MS, ALS, and epilepsy. However, studies have also found that Akkermansia can increase inflammation and suggest it may instead play a detrimental role in MS and PDD. Gut bacterial strains can be either beneficial or detrimental depending on microbial functions (e.g., vitamin or toxin production) or depending on disease-specific interactions (e.g., Bacteroides may be detrimental for AD but beneficial for MS). Studies have identified 4 clades of Akkermansia that exhibit pronounced differences in genomic and metabolic functions. These strain-specific differences have not been investigated in neurologic diseases, which is a major barrier in the discovery and implementation of Akkermansia-based therapeutics for AD/ADRD and other neurologic diseases. We have made several discoveries that support our exploration of Akkermansia strains in neurodegenerative diseases. We found that although Akkermansia is elevated in MS, it negatively correlates with disease severity, suggesting that elevated levels may be a compensatory mechanism to ameliorate disease. We then isolated novel strains of Akkermansia from MS patients and found that strain BWH-H3 has the greatest protective effect in EAE and decreased IL-17 producing gd T cells. We also found that administering Akkermansia to the SOD1G93A mouse model of ALS modulated genes known to be involved in the ALS pathogenesis, including Fus, as well as genes involved in protein degradation. Little is known about how Akkermansia affects the brain and we have found that mono-colonizing mice with Akkermansia modulated microglial phenotypes, which may have critical implications for AD/ADRD and other neurologic diseases. This project will create the largest collection of Akkermansia strains from patients with neurologic diseases and will characterize genomic differences between strains isolated from AD and PDD vs. strains isolated from nondementia neurologic diseases and healthy controls in Aim 1. Because Akkermansia strains can vary in vitamin secretion and other metabolic functions, we will characterize their metabolomic potential in Aim 2. Finally, we will test how different strains of Akkermansia can affect the 4 major cell types in the brain by colonizing germfree mice and performing RNAseq on sorted microglia, astrocytes, oligodendrocytes, and neurons in Aim 3. This R21 will create a valuable biologic resource of Akkermansia strains and provide mechanistic insight into host pathways in the brain that may be differentially modulated by Akkermansia in a strain-specific manner. This could ultimately pave the way for novel disease-specific therapeutics for AD, PDD, and other neurologic diseases.

肠道微生物群可以影响神经系统疾病，包括阿尔茨海默病（AD）、帕金森病痴呆（PDD）、多发性硬化症（MS）、肌萎缩侧索硬化症（ALS）和癫痫。然而，特定细菌的作用以及它们如何与AD和AD相关痴呆（ADRD）与非痴呆神经系统疾病的疾病特异性机制相关尚未探讨。嗜粘蛋白阿克曼氏菌已成为一种有益的微生物，具有治疗AD、MS、ALS和癫痫的潜力。然而，研究还发现阿克曼氏菌会增加炎症，并表明它可能在MS和PDD中发挥有害作用。肠道细菌菌株可以是有益的或有害的，这取决于微生物的功能（例如，维生素或毒素产生）或取决于疾病特异性相互作用（例如，拟杆菌可能对AD有害，但对MS有益）。研究已经确定了4个阿克曼氏菌分支，它们在基因组和代谢功能上表现出明显的差异。尚未在神经系统疾病中研究这些菌株特异性差异，这是发现和实施AD/ADRD和其他神经系统疾病的基于阿克曼氏病的治疗方法的主要障碍。我们已经取得了几项发现，支持我们在神经退行性疾病中探索阿克曼菌菌株。我们发现，虽然Akkermansia在MS中升高，但它与疾病严重程度呈负相关，表明升高的水平可能是改善疾病的补偿机制。然后，我们从MS患者中分离出阿克曼氏菌的新菌株，发现菌株BWH-H3在EAE中具有最大的保护作用，并减少产生IL-17的gd T细胞。我们还发现，将Akkermansia给予ALS的SOD 1G 93 A小鼠模型调节了已知参与ALS发病机制的基因，包括Fus，以及参与蛋白质降解的基因。关于Akkermansia如何影响大脑知之甚少，我们发现Akkermansia单克隆小鼠调节小胶质细胞表型，这可能对AD/ADRD和其他神经系统疾病具有重要意义。该项目将创建来自神经系统疾病患者的最大的阿克曼氏菌菌株集合，并将表征从AD和PDD分离的菌株与从Aim 1中的非痴呆神经系统疾病和健康对照分离的菌株之间的基因组差异。由于阿克曼氏菌菌株在维生素分泌和其他代谢功能方面可能存在差异，因此我们将在Aim 2中描述其代谢组学潜力。最后，我们将通过定殖无菌小鼠并对Aim 3中分选的小胶质细胞、星形胶质细胞、少突胶质细胞和神经元进行RNAseq，测试不同的阿克曼氏菌菌株如何影响脑中的4种主要细胞类型。这种R21将创造一个有价值的阿克曼氏菌株的生物资源，并提供在大脑中的宿主途径，可能是由阿克曼氏菌株特异性的方式差异调制的机制洞察。这可能最终为AD，PDD和其他神经系统疾病的新型疾病特异性治疗铺平道路。