Sodium oligomannate remodels gut redox adaptation and promotes microbiota-derived indole-3-propionic acid production to alleviate Alzheimer’s disease

Background Sodium oligomannate (GV-971), a microbiome-centric therapy for Alzheimer’s disease (AD) in China, shows variable clinical efficacy. Objective To investigate the mechanisms underlying the differential responsiveness to GV-971 in AD therapy. Methods Cognitive/functional outcomes, Aβ-PET imaging, stool metagenomics and plasma metabolomics were assessed in AD patients. Post-treatment faecal microbiota were transplanted into 5xFAD mice, followed by behavioural, pathological and single-nucleus transcriptomic analyses. Indole-3-propionic acid (IPA) supplementation and colonisation with wild-type or IPA-deficient C. sporogenes (ΔfldC) were performed to evaluate the impact of IPA in vitro and in vivo. Redox potential measurement and bacterial transcriptional and metabolic profiling were performed to assess the redox status. Results AD patients treated with GV-971 were stratified into improved and non-improved cognitive responses based on changes in ADAS-Cog11 scores, accompanied by concordant changes in cerebral Aβ burden. Improved patients showed a more reductive gut state, characterised by reduced microbial respiratory electron-transport potential. Faecal microbiota transplantation from improved donors recapitulated the therapeutic benefits of GV-971 in 5xFAD mice. Targeted metabolomic analyses across humans and mice identified microbiota-derived IPA as a key mediator of GV-971’s therapeutic responses. IPA enhanced microglial Aβ uptake and lysosomal clearance via an AhR-dependent pathway. GV-971 treatment enriched IPA-producing bacteria of the genus Clostridium, particularly C. sporogenes. Colonisation with C. sporogenes elevated circulating IPA levels and concomitantly ameliorated cognitive deficits and AD-related pathology. Mechanistically, GV-971 lowered the culture redox potential and promoted IPA production by C. sporogenes. This gut redox status and associated IPA production were further recapitulated in complex microbial communities, as evidenced by GV-971-treated mice. Conclusion GV-971 ameliorates AD by remodelling microbial redox metabolism to boost bacterial IPA production, which enhances AhR-mediated microglial Aβ clearance and underpins its therapeutic efficacy.