Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models

Caroline Wasén, Leah C. Beauchamp, Julia Vincentini, Shuqi Li, Danielle S. LeServe, Christian Gauthier, Juliana R. Lopes, Thais G. Moreira, Millicent N. Ekwudo, Zhuoran Yin, Patrick da Silva, Rajesh K. Krishnan, Oleg Butovsky, Laura M. Cox () and Howard L. Weiner ()
Additional contact information
Caroline Wasén: Brigham & Women’s Hospital, Harvard Medical School
Leah C. Beauchamp: Brigham & Women’s Hospital, Harvard Medical School
Julia Vincentini: Brigham & Women’s Hospital, Harvard Medical School
Shuqi Li: Brigham & Women’s Hospital, Harvard Medical School
Danielle S. LeServe: Brigham & Women’s Hospital, Harvard Medical School
Christian Gauthier: Brigham & Women’s Hospital, Harvard Medical School
Juliana R. Lopes: Brigham & Women’s Hospital, Harvard Medical School
Thais G. Moreira: Brigham & Women’s Hospital, Harvard Medical School
Millicent N. Ekwudo: Brigham & Women’s Hospital, Harvard Medical School
Zhuoran Yin: Brigham & Women’s Hospital, Harvard Medical School
Patrick da Silva: Brigham & Women’s Hospital, Harvard Medical School
Rajesh K. Krishnan: Brigham & Women’s Hospital, Harvard Medical School
Oleg Butovsky: Brigham & Women’s Hospital, Harvard Medical School
Laura M. Cox: Brigham & Women’s Hospital, Harvard Medical School
Howard L. Weiner: Brigham & Women’s Hospital, Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-β (Aβ) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aβ plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aβ1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aβ clearance and accumulation of amyloid plaques.

Date: 2024
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DOI: 10.1038/s41467-024-47683-w

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