Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden.
Nat Commun. 2024 May 8;15(1):3872. doi: 10.1038/s41467-024-47683-w.
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.
肠道微生物群和小胶质细胞在阿尔茨海默病（AD）中起着关键作用，而双歧杆菌的升高与 AD 患者的脑脊液淀粉样蛋白-β（Aβ）和tau 水平相关。我们假设双歧杆菌通过调节小胶质细胞来促进 AD 的发生。在这里，我们发现给 APP/PS1-21 小鼠施用脆弱拟杆菌会增加雌性小鼠的 Aβ斑块，调节皮质淀粉样蛋白加工基因的表达，并下调小胶质细胞吞噬和蛋白降解的基因表达。我们进一步发现，给老年野生型雄性和雌性小鼠施用脆弱拟杆菌会抑制 Aβ1-42 注入海马后小胶质细胞的摄取。用甲硝唑耗竭鼠拟杆菌可降低 5xFAD 小鼠的淀粉样蛋白负荷，并激活与吞噬、细胞因子信号和溶酶体降解相关的小胶质细胞途径。总之，我们的研究表明，拟杆菌门的成员通过抑制小胶质细胞的吞噬功能来促进 AD 的发病机制，从而导致 Aβ清除受损和淀粉样斑块的积累。
