Tryptophan–kynurenine metabolic reprogramming along the gut–brain axis alleviates Alzheimer’s pathology

The gut–brain axis influences neuroinflammation and metabolic homeostasis in Alzheimer’s disease (AD). Disruption of gut microbiota and barrier function promotes amyloid and tau pathology via immune and metabolic dysregulation. In this study, Limosilactobacillus fermentum SRK414 (SRK414) was orally administered to ADLPAPT mice, resulting in reduced Aβ and tau pathology and improved cognition. Multi-omics analysis revealed that SRK414 altered gut microbial composition and increased hippocampal kynurenic acid (KYNA), a metabolite linked to neuroimmune regulation. Increased hippocampal KYNA was associated with metabolic changes consistent with enhanced neuronal fatty acid oxidation, reduced lipid accumulation, and suppressed microglial activation, suggesting improved hippocampal homeostasis. In vitro studies further showed that KYNA attenuated tau-related and inflammatory phenotypes. These findings support a link between gut microbial modulation and brain resilience, and suggest that KYNA may contribute to the neuroprotective effects associated with SRK414 treatment. This study highlights metabolites modulated by SRK414 administration as potential mediators of microbiota-based therapeutic effects in AD.