The human gut microbiota undergoes substantial compositional and functional shifts with aging and Alzheimer’s disease (AD). While associations between bacterial species and disease risk are increasingly recognized, functional heterogeneity at the strain level remains poorly understood. Here, we examined whether strain-level variation within Phocaeicola dorei, a common human gut commensal bacterium that is elevated in AD, differentially influences host immunity and neurodegenerative outcomes.
We compared a P. dorei strain isolated from an individual with AD to a strain isolated from a healthy control. In vitro, the healthy control strain enhanced macrophage-mediated Aβ uptake, whereas the AD-derived strain failed to stimulate phagocytosis. In vivo colonization of APP/PS1 mice revealed that the AD-derived strain impaired spatial memory in females, increased Aβ plaque burden, and reduced microglial density in affected brain regions, accompanied by elevated peripheral inflammatory T cell responses. Microglial transcriptomic profiling indicated that colonization with the AD-derived strain altered metabolic activation states.
Whole-genome sequencing identified the absence of wbyH, encoding a putative O-antigen biosynthesis protein, in the AD-derived strain. Consistent with this genomic difference, SDS-PAGE analysis revealed structural divergence in lipopolysaccharide (LPS) between strains. In vitro and in vivo characterization of the LPS isolated from these unique strains demonstrated functional differences in induction of Ab phagocytosis in macrophages and microglia between strains, mediated through TLR4. Metabolomic profiling further showed that the healthy control strain retained the capacity to synthesize vitamins B1 and B6, whereas the AD-derived strain lacked these pathways and was associated with depletion of neuroprotective lipids and accumulation of neurotoxic metabolites in the brain.
Together, these findings demonstrate that strain-specific genomic and metabolic features of gut bacteria critically shape host immune responses and disease-relevant outcomes, underscoring the importance of strain-level resolution in microbiome research and highlighting the gut microbiota as a modifiable contributor to Alzheimer’s disease progression.