Exploring Akkermansia Genomic and Functional Diversity in Neurologic Diseases

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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.