Exploring Akkermansia Genomic and Functional Diversity in 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）与非痴呆性神经疾病的疾病特异性机制相关尚不清楚。嗜muciniphila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，Akkermansia会增加炎症，并表明它可能在MS和PDD中发挥有害作用。肠道细菌菌株可能是有益的，也可能是有害的，这取决于微生物的功能（例如，维生素或毒素的产生）或取决于疾病特异性的相互作用（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Akkermansia分支，它们在基因组和代谢功能上表现出明显的差异。这些菌株特异性差异尚未在神经系统疾病中得到研究，这是发现和实施基于akkermansia的治疗AD/ADRD和其他神经系统疾病的主要障碍。我们已经有了一些发现，支持我们对Akkermansia菌株在神经退行性疾病中的探索。我们发现，尽管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代偿机制。然后，我们从MS患者中分离出新的Akkermansia菌株，发现菌株BWH-H3对EAE具有最大的保护作用，并减少IL-17的产生。我们还发现，将Akkermansia给予SOD1G93A小鼠模型中已知参与ALS发病机制的调节基因，包括Fus，以及参与蛋白质降解的基因。我们对Akkermansia如何影响大脑知之甚少，我们发现患有Akkermansia的单定植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Akkermansia菌株集合，并将在Aim 1中描述从AD和PDD分离的菌株与从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。因为Akkermansia菌株在维生素分泌和其他代谢功能上可以改变，我们将在Aim 2中描述它们的代谢组学潜力。最后，我们将在Aim 3中通过定殖无菌小鼠并对分选的小胶质细胞、星形胶质细胞、少突胶质细胞和神经元执行RNAseq来测试不同菌株Akkermansia如何影响大脑中的4种主要细胞类型。该R21将为Akkermansia菌株创造有价值的生物资源，并为Akkermansia以菌株特异性方式差异调节宿主大脑通路提供机制见解。这可能最终为阿尔茨海默病、PDD和其他神经系统疾病的新型疾病特异性治疗铺平道路。

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.