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

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. • An imbalance of Clostridium and Bacteroides is a key feature linked to Aβ burden • Supplementation of B. ovatus ameliorates AD pathologies • Microbial-associated metabolite (LPC) ameliorates AD pathologies • LPC inhibits ferroptosis through the orphan receptor GPR119 in an AD mouse model Zha et al. reveal that dysbiosis, resulting from the loss of beneficial microbiota species, acts as a contributing factor in the pathogenesis of an AD mouse model. B. ovatus -triggered LPC-GPR119-ferroptosis axis ameliorates the symptoms of AD, showing potential for AD treatment.