Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation. Original paper

What was studied?

This study investigated how the gut microbiome regulates Alzheimer’s disease (AD) pathologies and cognitive impairment using the 3xTg-AD mouse model. The focus was on microbiome-driven shifts in polyunsaturated fatty acid metabolism, especially arachidonic acid–derived inflammatory lipids, and their impact on the C/EBPβ–AEP (asparagine endopeptidase) pathway, a key driver of amyloid-β and tau cleavage. Analyses included longitudinal microbiome profiling, comparisons between germ-free and specific-pathogen-free mice, fecal microbiota transplantation (FMT) from AD patients and healthy donors, hippocampal RNA-seq, and metabolomics (faeces, serum, and brain). The work emphasises how gut dysbiosis, including Bacteroides enrichment, promotes inflammatory PUFA metabolites that activate microglia and accelerate hallmark AD lesions.

Who was studied?

Experimental models included germ-free, specific-pathogen-free, and human-microbiota-associated 3xTg mice. Human fecal donors were older adults (≥65 years) from nursing facilities, including individuals with clinically diagnosed AD and cognitively healthy controls. All mice were female to control for sex-based microbiome variability. Human-derived microbial communities were successfully engrafted into germ-free mice, allowing evaluation of the causal effects of AD-associated microbiota on neuroinflammation, PUFA metabolism, microglial activation, and cognitive performance.

Most important findings

Loss of gut microbiota dramatically reduced AD pathology, where germ-free mice showed far lower Aβ, Thioflavin-S–positive plaques, AT8-positive tau, and T22-positive tau oligomers. Metabolomics demonstrated substantial reductions in arachidonic-acid–derived metabolites in germ-free mice. Transcriptomics revealed broad downregulation of inflammatory and arachidonic-acid pathways. AD-donor FMT produced powerful pathological effects: ex-germ-free mice colonised with AD microbiota showed increases in Aβ42, tau phosphorylation, microglial activation, and worsening performance on Y-maze cognitive testing. Enrichment of Bacteroides intestinalis, B. fragilis, and B. xylanisolvens aligned with elevated secretion of arachidonic-acid metabolites in vitro. These microbial strains generated PGE2, LTB4, and 12-HHT, directly linking microbiome structure with PUFA-driven neuroinflammation. SCFA supplementation activated the C/EBPβ–AEP axis and worsened AD pathology in germ-free mice, while PGE2-G (a key inflammatory PUFA derivative) amplified microglial maturation.

Key implications

These results show that gut dysbiosis is not just correlated with AD but functionally contributes to its pathogenesis through PUFA-associated neuroinflammation. Specific microbial taxa—especially Bacteroides species with PUFA-metabolising capacity—appear central in producing inflammatory lipids that activate microglia and drive AEP-dependent cleavage of APP and tau. Clinically, this work strengthens the rationale for microbiome-targeted therapies, including dietary modulation of PUFA metabolism, probiotics promoting butyrate-producing species, personalised microbiota restructuring, and potentially carefully selected fecal transplants. Importantly, microbiome signatures involving Bacteroides elevation, reduced Firmicutes, decreased butyrate producers, elevated PGE2/LTB4–pathway activity, and activation of the C/EBPβ–AEP axis emerge as relevant biomarkers for microbiome-based AD risk stratification.

Citation

Chen C, Liao J, Xia Y, et al. Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation.Gut. 2022;71(11):2233-2252. doi:10.1136/gutjnl-2021-326269