Microbiota-derived lysophosphatidylcholine alleviates Alzheimer's disease pathology via suppressing ferroptosis

Cell Metab. 2025 Jan 7;37(1):169-186.e9. doi: 10.1016/j.cmet.2024.10.006. Epub 2024 Nov 6.

Abstract

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.

Keywords: Alzheimer’s disease; Bacteroides ovatus; GPR119; ferroptosis; gut microbiota; lysophosphatidylcholine; β-amyloid.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / microbiology
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Disease Models, Animal
  • Female
  • Ferroptosis* / drug effects
  • Gastrointestinal Microbiome* / drug effects
  • Humans
  • Lysophosphatidylcholines* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic

Substances

  • Lysophosphatidylcholines
  • Amyloid beta-Peptides