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.

肠道微生物区系可以影响神经系统疾病，包括阿尔茨海默病(AD)、帕金森氏病痴呆(PDD)、多发性硬化症(MS)、肌萎缩侧索硬化症(ALS)和癫痫。然而，在AD和AD相关痴呆(ADRD)与非痴呆性神经疾病中，特定细菌的作用及其与疾病特定机制的关系尚未被探索。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，研究也发现阿克曼草会增加炎症，并表明它可能反而在多发性硬化症和PDD中发挥有害作用。肠道细菌菌株可以是有益的，也可以是有害的，这取决于微生物的功能(例如，维生素或毒素的产生)或取决于疾病的特定相互作用(例如，类杆菌可能对AD有害，但对MS有益)。研究已经确定了阿克曼属的4个分支，它们在基因组和代谢功能上表现出显著的差异。这些菌株特异性差异尚未在神经系统疾病中进行研究，这是发现和实施以阿克曼西亚为基础的治疗AD/ADRD和其他神经系统疾病的主要障碍。我们已经有了几项发现，支持我们探索阿克曼氏菌株在神经退行性疾病中的作用。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，提示升高的水平可能是改善疾病的一种代偿机制。然后我们从MS患者中分离出新的阿克曼氏菌株，发现BWH-H3株对EAE具有最大的保护作用，并减少IL-17产生的gd T细胞。我们还发现，在ALS的SOD1G93A小鼠模型中，给予Akkermansia调制了已知的参与ALS发病的基因，包括FUS，以及参与蛋白质降解的基因。目前对Akkermansia如何影响大脑知之甚少，我们发现Akkermansia的单一定植小鼠调节了小胶质细胞的表型，这可能对AD/ADRD和其他神经系统疾病具有关键意义。该项目将创建来自神经系统疾病患者的最大阿克尔马氏菌菌株集合，并将在目标1中表征从AD和PDD分离的菌株与从非痴呆性神经疾病和健康对照组分离的菌株之间的基因组差异。由于阿克马氏菌菌株在维生素分泌和其他代谢功能方面存在差异，我们将在目标2中表征它们的代谢潜力。最后，我们将通过在无菌小鼠中定植并对分离的小胶质细胞、星形胶质细胞、少突胶质细胞进行RNAseq来测试不同的Akkermansia菌株如何影响大脑中的四种主要细胞类型。R21将为Akkermansia菌株创造一个宝贵的生物资源，并提供对大脑中可能由Akkermansia以菌株特异性方式差异调制的宿主路径的机械性洞察。这最终可能为AD、PDD和其他神经系统疾病的新型疾病特异性疗法铺平道路。