Microbiome‐associated metabolic determinants of neurodegeneration and cognitive resilience

Abstract Background Type 2 diabetes (T2D) is a common antecedent of pathological neurodegeneration and accompanying dementia, including Alzheimer’s Disease (AD); however, the mechanistic link between metabolic and neurodegenerative disorders remains unresolved (1‐3). Study of a small cohort of dementia patients revealed divergent gut microbiota composition, increased gut permeability, and inflammation, implicating a microbial determinant in neuroimmune dysregulation (4), an emerging player in neurodegeneration (5). Notably, the microbiome is a source of neuroprotective metabolites (6), highlighting the need to elucidate the role of the microbiome and realize the potential for its therapeutic modulation in AD. We recently began a clinical trial focusing on individuals of Mexican descent living in Southern Texas, a population with increased prevalence of co‐morbid T2D and early onset AD (7‐8), with the working hypothesis that diet‐driven shifts in gut microbiome composition contribute to T2D and AD pathophysiology in this population (9‐11). Method We will perform metagenomic 16S rRNA gene amplicon sequencing and compare within (alpha) and between (beta) sample diversity as well as quantitative phylogenetic and taxonomic comparisons. Using 3xTg‐AD and hTau mouse models, we will determine the impact of microbial depletion via broad spectrum antibiotics on AD pathology and cognitive function. Data will be analyzed separately for each sex using nested t‐tests, nested one‐way ANOVA, or a mixed effects model to account for litter effects. Result Data resulting from our preclinical animal and clinical human studies will inform future experiments in which we will transplant fecal microbiota samples derived from T2D versus non‐diabetic human subjects into microbially‐depleted, “humanized” AD mice. We will then perform metabolomic, molecular, electrophysiological, and behavioral analyses to determine the impact(s) of T2D gut microbiota on host AD‐like pathology and behavioral phenotypes. Conclusion Characterizing gut microbiome signatures of T2D individuals of Mexican descent living in Southern Texas could identify key actors among “disease state” microbiota which may exacerbate or accelerate neurodegenerative disorders, as well as gut microbiota present in healthy controls lost in the T2D population which contribute to molecular mechanisms of cognitive resilience. Consequently, our approach may lead to novel immunotherapeutic approaches to target or limit neuroinflammation in AD.