The neuro-immuno-metabolic axis of exercise: a unified mechanistic framework for exercise-induced cognitive enhancement and psychological resilience

Physical exercise is widely recognized for promoting cognitive function and psychological resilience; however, the precise systemic mechanisms remain fragmented across isolated disciplines. Existing models often fail to capture the complex, multi-systemic nature of these adaptations.

We conducted a comprehensive literature search in PubMed, Web of Science, and Scopus databases up to December 2025. Keywords included "exercise," "neuroinflammation," "metabolism," "kynurenine pathway," and "gut-brain axis." We prioritized high-quality preclinical and clinical studies that examined bidirectional cross-talk between at least two physiological systems (neural, immune, or metabolic) to construct a unified theoretical synthesis.

Based on this synthesis, we propose the "Neuro-Immuno-Metabolic (NIM) Axis." Unlike linear bipartite models, this framework positions exercise as a systemic "energy challenge" that triggers a coordinated recalibration. Key mechanisms identified include: (1) Metabolic Signaling: Lactate, ketone bodies, and the PGC-1α-mediated kynurenine detoxification pathway act as systemic signalers; (2) Immune Regulation: Exercise drives a shift from pro-inflammatory surveillance to "repair-oriented inflammation" rather than binary M1/M2 phenotypes; and (3) Gut-Brain Integration: Gut metabolites (e.g., indoles, SCFAs) regulate central immune tolerance via AhR signaling. Furthermore, we delineate the mechanistic specificity of aerobic, resistance, and high-intensity interval training (HIIT).

The NIM axis provides a novel, integrative framework that explains how metabolic stress is transduced into psychological resilience. These insights establish a theoretical foundation for precision exercise medicine and advocate for future multi-omics research to develop individualized interventions.