Exploring the Microbiome-Kynurenine Axis in Mild Cognitive Impairment: From Gut to Brain.

Abstract

Mild cognitive impairment (MCI) represents a critical prodromal stage of Alzheimer's disease. This review synthesizes current evidence to present a coherent pathological cascade driving MCI progression: gut microbiota dysbiosis (e.g., enrichment of Prevotella and depletion of Akkermansia) triggers a butyrate deficit and compromise of intestinal integrity, leading to systemic inflammation. This inflammatory milieu upregulates indoleamine 2,3-dioxygenase 1 (IDO1), shifting tryptophan metabolism toward the kynurenine pathway and resulting in the dominance of neurotoxic branches (3-hydroxykynurenine [3-HK], quinolinic acid [QUIN]) over neuroprotective kynurenic acid (KYNA). This metabolic imbalance promotes N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity, oxidative stress, and neuroinflammation, which collectively precipitate synaptic dysfunction and cognitive decline. We explicitly highlight this "gut-immune-metabolic" vicious cycle as the core framework of MCI pathology. Targeting this cycle through a dual strategy-restoring microbial diversity and pharmacologically inhibiting the IDO1/kynurenine 3-monooxygenase (KMO) enzymes-represents a promising therapeutic approach to delay the transition from MCI to dementia.