Microbial determinants of dementia risk in subjects of Mexican descent with type 2 diabetes living in South Texas

Type 2 diabetes (T2D) is a common forerunner of neurodegeneration and dementia, including Alzheimers Disease (AD), yet the underlying mechanisms remain unresolved. Individuals of Mexican descent living in South Texas have increased prevalence of comorbid T2D and early onset AD, despite low incidence of the predisposing APOE-{chi}4 variant and an absence of the phenotype among relatives residing in Mexico - suggesting a role for environmental factors in coincident T2D and AD susceptibility. Here, in a small clinical trial, we show dysbiosis of the human gut microbiome could contribute to neuroinflammation and risk for AD in this population. Divergent Gastrointestinal Symptom Rating Scale (GSRS) responses, despite no differences in expressed dietary preferences, provided the first evidence for altered gut microbial ecology among T2D subjects (sT2D) versus population-matched healthy controls (HC). Metataxonomic 16S rRNA sequencing of participant stool revealed a decrease in alpha diversity of sT2D versus HC gut communities and identified BMI as a driver of gut community structure. Linear discriminant analysis effect size (LEfSe) identified a significant decrease in the relative abundance of the short-chain fatty acid-producing taxa Lachnospiraceae, Faecalibacterium, and Alistipes and an increase in pathobionts Escherichia-Shigella, Enterobacter, and Clostridia innocuum among sT2D gut microbiota, as well as differentially abundant gene and metabolic pathways. These results suggest characterization of the gut microbiome of individuals with T2D could identify key actors among "disease state" microbiota which may increase risk for or accelerate the onset of neurodegeneration. Furthermore, they identify candidate microbiome-targeted approaches for prevention and treatment of neuroinflammation in AD. ImportanceMexican Americans are at increased risk for developing type 2 diabetes (T2D) that precedes Alzheimers Disease (AD), compared to non-Hispanic whites; however, the reason remains unknown. The leading risk factor for T2D is obesity. Among Texans, individuals of Mexican descent are disproportionately affected by obesity and T2D. Mexican immigrants to the US and their descendants face significant environmental pressures, including dietary changes. Diet is the primary determinant of gut microbiome composition, which is increasingly linked to both metabolic and brain health. Here, we performed a case-control, cross-sectional observational clinical study to test the hypothesis that diet-driven shifts in gut microbiome composition contribute to T2D and AD susceptibility in individuals of Mexican descent living in South Texas. Our results identify a microbial signature, characterized by decreased short-chain fatty acid producers with an increase in opportunistic pathogenic species, that could contribute to the increased risk for neurodegenerative disorders among individuals with T2D.