What this is
- This review constructs a unified framework called the Neuro-Immuno-Metabolic () Axis, integrating how exercise influences cognitive function and psychological resilience.
- It synthesizes findings across various disciplines to highlight the complex, systemic interactions triggered by physical activity.
- Key mechanisms include metabolic signaling, immune regulation, and gut-brain integration, which collectively enhance brain health.
Essence
- The Axis framework elucidates how exercise acts as a systemic energy challenge, promoting cognitive enhancement and psychological resilience through interconnected metabolic, immune, and neural pathways.
Key takeaways
- Exercise enhances cognitive function and mental health through a complex interplay of metabolic, immune, and neural mechanisms. This review emphasizes the need for a holistic understanding of these interactions.
- The Axis challenges traditional views of inflammation, presenting it as a dual process that can be both protective and detrimental. This perspective allows for targeted therapeutic strategies to harness beneficial inflammatory responses.
- Recognizing the distinct effects of various exercise modalities on the Axis supports personalized exercise prescriptions, optimizing cognitive and psychological outcomes across different populations.
Caveats
- The review relies on existing literature, which may have inherent biases or limitations in study designs. Future research is needed to validate the proposed Axis framework.
- Individual variability in response to exercise is acknowledged, yet the mechanisms underlying this variability require further exploration to enhance personalized interventions effectively.
Definitions
- Neuro-Immuno-Metabolic (NIM) Axis: A framework that integrates neural, immune, and metabolic systems to explain the effects of exercise on cognitive and psychological health.
Simplified
Introduction
The positive impact of physical exercise on cognitive function and mental health has been extensively documented across diverse populations, age groups, and clinical conditions. It underscores exercise’s significance as a non-pharmacological intervention to enhance brain health and psychological well-being. Clinical and observational studies confirm that exercise improves specific cognitive domains including memory, executive function, attention, and cognitive flexibility. Benefits are observed in healthy individuals, older adults, adolescents, and patients with neurodegenerative or psychiatric disorders (Cohn-Schwartz, 2020; Smith and Merwin, 2021; Xu et al., 2024). For instance, narrative reviews highlight that physical activity enhances cerebral blood flow. It stimulates neurotrophic factor synthesis and reduces oxidative stress and inflammation. These effects collectively contribute to improved memory and executive functioning in adults and academic performance in younger populations (Biazus-Sehn et al., 2020; Pujari, 2024). These neurobiological effects are accompanied by mood-regulating benefits. Activation of the endocannabinoid system and release of endorphins mediate these benefits, alleviating symptoms of anxiety and depression. In addition, exercise has been investigated as an adjunctive therapy in mental illnesses such as major depressive disorder (MDD), generalized anxiety disorder, schizophrenia, bipolar disorder, and eating disorders. It improves treatment efficacy and overall quality of life (Herbert et al., 2020; Pujari, 2024).
Multimodal brain imaging advances have further elucidated structural and functional brain adaptations. These changes underpin exercise-induced improvements in cognition and mental health (Valk et al., 2022). Cross-sectional studies using multimodal imaging techniques yield key findings. Individuals with regular exercise habits show greater gray matter volume in frontal and hippocampal regions. They also exhibit enhanced white matter integrity and more robust functional network configurations in key brain networks such as the default mode network (Yao et al., 2024). Notably, these neural correlates are associated with lower levels of depression and anxiety. They also link to higher life satisfaction, emphasizing the role of an active lifestyle in fostering psychological resilience and cognitive robustness. Such findings contribute to a growing body of evidence supporting exercise as a vital component in mental health promotion and cognitive maintenance (Gray et al., 2020; Zhao et al., 2020).
In clinical populations, structured exercise interventions have demonstrated efficacy in ameliorating physical and mental health outcomes. For example, randomized controlled trials implemented balance and muscle-strengthening programs during the COVID-19 pandemic. These included the Otago Exercise Programme for elderly individuals with cognitive frailty. The trials showed significant improvements in physical function, reduced depressive symptoms, and enhanced mental health-related quality of life (He et al., 2025; Kamiya et al., 2025; Tuan et al., 2024). Furthermore, among adolescents, both chronic participation in sports and acute bouts of exercise yield benefits in mental health and executive functioning. Differential effects are observed based on sport type and exercise intensity (Pasquerella et al., 2025; Song et al., 2024). These age- and condition-specific findings underscore the importance of tailoring exercise interventions to optimize cognitive and psychological outcomes.
Extensive reviews confirm physical activity’s protective effects against age-related cognitive decline. These studies highlight benefits of aerobic, resistance, and combined training modalities in older adults (Dos Santos et al., 2020; Zare et al., 2025). Moderate-intensity aerobic exercise (typically defined as 64–76% of maximum heart rate) enhances memory, executive function, and mood regulation. It potentially acts via increased hippocampal neurogenesis and elevated brain-derived neurotrophic factor (BDNF) levels (Antunes et al., 2020; Enette et al., 2020). Resistance training acutely improves visuospatial processing and executive functions. Chronic resistance regimens promote neurogenesis and enhance cerebral blood flow to prefrontal regions. Importantly, findings related to concurrent training are heterogeneous. Emerging evidence suggests that combining concurrent exercise with cognitive tasks yields superior cognitive and mental health benefits compared to aerobic exercise alone (Balbim et al., 2024; Dhahbi et al., 2025; Kraemer and Kraemer, 2023). These insights advocate for incorporating diverse exercise modalities in geriatric cognitive health strategies.
Meta-analyses and umbrella reviews further consolidate the evidence base. They demonstrate that exercise interventions produce small to moderate cognitive improvements across age groups and health statuses. Notably, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), exercise enhances cognitive flexibility, inhibitory control, and inattention symptoms. Effects on emotional and social functioning remain less robust (Dastamooz et al., 2023). Exercise’s impact on cognitive domains is influenced by multiple factors. These include exercise type, intensity, duration, and frequency. Individual characteristics such as sex and genetic polymorphisms (e.g., the BDNF Val66Met variant) are also key (Liu et al., 2020; Ludyga et al., 2020). These findings call for further research to delineate optimal exercise prescriptions and mechanisms underlying individual variability in response.
Central to the neurobiological mechanisms of exercise-induced cognitive enhancement is the role of BDNF. This neurotrophin is critical for synaptic plasticity, neurogenesis, and neuronal survival. Exercise elevates peripheral and central BDNF levels. This elevation correlates with improved cognitive function in healthy individuals. It also benefits patients with cognitive impairments such as mild cognitive impairment and Alzheimer’s disease (Huang et al., 2021; Oyovwi et al., 2025). Experimental studies reveal that exercise modulates epigenetic markers such as H3K9me3 at BDNF promoter regions. This regulation of BDNF expression occurs in an age-dependent manner (Ionescu-Tucker et al., 2021). Additionally, BDNF mediates exercise-induced shifts in amyloid precursor protein processing. It reduces Alzheimer’s disease pathology and enhances recognition memory (Baranowski et al., 2023). These molecular adaptations highlight BDNF as a key integrator of exercise effects on brain plasticity and cognitive resilience.
Beyond BDNF, exercise exerts multifaceted effects through neuroimmune and metabolic pathways. It challenges the traditional view of neuroinflammation as solely detrimental. The concept of “repair-oriented” or “resolving” inflammation has emerged. Exercise modulates immune responses through this concept to promote neuroprotection and tissue repair. For instance, exercise increases regulatory T cell populations. These populations facilitate white matter repair post-stroke (Mu et al., 2025). Exercise also modulates microglial lipid metabolism via the AMPK-PGC1α-PPARγ pathway. This modulation attenuates neuroinflammation after spinal cord injury (Ying et al., 2025). Exercise further orchestrates systemic metabolic and neuroimmune homeostasis via the brain-muscle-liver axis. It enhances mitochondrial function, reduces oxidative stress, and balances pro- and anti-inflammatory cytokines. These effects slow aging and neurodegeneration (Kong et al., 2025).
Recent advances have expanded understanding of the gut-brain-muscle axis. They reveal bidirectional communication among the central nervous system, skeletal muscle, and gut microbiota. Specifically, exercise influences gut microbial composition and metabolite production. These changes in turn modulate muscle metabolism, neuroinflammation, and cognitive function (Cutuli et al., 2023; Morella et al., 2023; Ribeiro et al., 2022). Myokines produced during muscle contraction mediate these effects. Key examples include irisin and BDNF. These myokines promote neuroplasticity and systemic health (Nicastri et al., 2022; Wang et al., 2022). This integrative perspective underscores the complexity of exercise’s neurobiological impact. It involves neuro-immune-metabolic crosstalk across multiple organ systems.
Importantly, the efficacy of exercise in enhancing cognition and mental health is influenced by exercise modality, intensity, duration, and individual factors. Network meta-analyses identify effective mind–body exercise modes. Pilates and Tai Chi benefit chronic non-specific low back pain and cognitive function (Shi et al., 2022). Similarly, high-intensity training improves outcomes in chronic nonspecific low back pain (Verbrugghe et al., 2020). Acute vigorous exercise elevates lactate and BDNF levels more than moderate exercise, leading to greater cognitive benefits (Waddington et al., 2024). Moreover, sex differences modulate exercise-induced cognitive and molecular responses, necessitating sex-specific exercise recommendations (Kotecki and Bradford, 2022; Short et al., 2022). These findings advocate for precision exercise medicine, tailoring interventions to optimize neurobiological and psychological outcomes.
In summary, the accumulated evidence reveals that physical exercise enhances cognitive function and mental health through a complex, integrated neuro-immune-metabolic axis. Central mechanisms include modulation of neurotrophic factors such as BDNF. They also involve regulation of immune cell function and inflammation, metabolic reprogramming, and gut-brain-muscle interactions. This multidimensional framework transcends traditional unifactorial models. It supports a unified “neuro-immune-metabolic axis” as the core mechanism underlying exercise-induced cognitive and psychological resilience. Crucially, recognizing the heterogeneity of exercise effects across populations and modalities is critical for developing personalized interventions. Future research integrating multi-omics technologies, longitudinal designs, and advanced imaging will be essential to unravel the precise molecular pathways and optimize exercise prescriptions for brain health across the lifespan.
Search strategy
Search strategy and selection criteria to ensure a comprehensive synthesis, we conducted a systematic search of PubMed, Web of Science, and Scopus databases for articles published up to December 2025. Search terms included combinations of “exercise,” “neuroinflammation,” “metabolism,” “kynurenine,” “microglia,” “gut-brain axis,” and “cognitive function.” We prioritized studies that (1) examined bidirectional cross-talk between at least two systems (neural, immune, metabolic); (2) provided mechanistic insights rather than purely descriptive outcomes; and (3) included high-quality randomized controlled trials (RCTs) or well-controlled animal models. Articles lacking full text or not published in English were excluded.
Exercise as an energy challenge: recalibration of central and peripheral metabolic communication
Metabolic signaling molecules induced by exercise and their neural actions
Exercise induces a profound metabolic challenge. It necessitates coordinated communication between peripheral tissues and the central nervous system (CNS) to maintain energy homeostasis. Key metabolites generated during exercise include lactate and ketone bodies. These serve as essential signaling molecules that traverse the blood–brain barrier (BBB) to modulate neuronal energy supply and function (Jang et al., 2023; Jensen et al., 2020; Plourde et al., 2024; Versele et al., 2020). Lactate is produced by active skeletal muscle through anaerobic glycolysis. It is transported into the brain via monocarboxylate transporters (MCTs) such as MCT1 and MCT4. Within the brain, lactate acts as an alternative fuel substrate for neurons and astrocytes. This support sustains synaptic activity and cognitive processes during and after exercise (Murphy et al., 2020). Similarly, ketone bodies including β-hydroxybutyrate form during prolonged or intense exercise. They cross the BBB and contribute to neuronal energy metabolism. This is particularly relevant when glucose availability is limited (Opialla et al., 2022). Beyond fuel provision, these metabolites function as signaling entities. They influence gene expression and neural plasticity in the CNS.
A central molecular mediator of exercise-induced neural adaptation is peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Exercise robustly upregulates PGC-1α expression in skeletal muscle. This upregulation in turn induces the expression of fibronectin type III domain-containing protein 5 (FNDC5) (Ali et al., 2024; Jo and Song, 2021; Pignataro et al., 2021). FNDC5 undergoes cleavage to release irisin, a myokine that enters the CNS. Irisin promotes the expression of BDNF. BDNF is a pivotal neurotrophin involved in synaptic plasticity and cognitive enhancement (Murphy et al., 2020; Zalouli et al., 2023). The PGC-1α/FNDC5/irisin axis thus acts as a molecular conduit. It links peripheral metabolic activity to central neural plasticity adaptations (Lee et al., 2025; Leger et al., 2024).
Beyond the PGC-1α-FNDC5-irisin axis, exercise-induced metabolic adaptations also exert neuroprotection through the regulation of the tryptophan-kynurenine pathway. Skeletal muscle PGC-1α upregulation stimulates the expression of kynurenine aminotransferases (KATs), enzymes that catalyze the peripheral conversion of kynurenine into kynurenic acid (KYNA). This conversion is critical because, unlike kynurenine, KYNA cannot cross the blood–brain barrier. By shifting the metabolic flux towards KYNA, exercise effectively reduces the availability of kynurenine for transport into the CNS, thereby preventing its central metabolism into the neurotoxic agonist quinolinic acid (QUIN). This mechanism functions as a “peripheral detoxification” system, shielding the brain from excitotoxicity and stress-induced inflammation, and provides a distinct metabolic link between muscle bioenergetics and psychological resilience (Agudelo et al., 2014; Allison et al., 2019).
Moreover, metabolic signals and neurotrophic factors such as BDNF exhibit synergistic regulation during exercise. BDNF expression is enhanced in response to metabolic changes. These changes include increased lactate and ketone levels. This enhancement facilitates synaptogenesis and remodeling of neural networks. Such networks are critical for learning and memory (Zalouli et al., 2023). This coordinated upregulation supports synapse formation and strengthening, thereby potentially facilitating the optimization of cognitive function. Collectively, these findings underscore the role of exercise-induced metabolites and myokines. They mediate neuroenergetic support and neural plasticity through integrated peripheral-central signaling pathways (Ajoy et al., 2021; Spanaki et al., 2024; Vezzoli et al., 2020) (Table 1).
| Molecule name | Core functions | Targets | Primary evidence source | References |
|---|---|---|---|---|
| Lactate | Neuronal energy substrate, BDNF regulation | Hippocampal neurons, MCT1/MCT4 transporters | Human & animal | ,, and [Murphy et al. (2020)] [Plourde et al. (2024)] [Vezzoli et al. (2020)] |
| PGC-1α/irisin | Peripheral-central neural plasticity linkage | Skeletal muscle, central BDNF promoter | Animal (preclinical) | ,, and [Ali et al. (2024)] [Lee et al. (2025)] [Leger et al. (2024)] |
| IL-6 (myokine) | IL-10 induction, repair-oriented inflammation initiation | Peripheral immune cells, microglia | Animal (preclinical) | ,, and [Liu et al. (2024)] [Mao et al. (2020)] [Stojanovic et al. (2025)] |
| SCFAs (acetate/propionate/butyrate) | Neuroinflammation inhibition, neurogenesis promotion | Microglia, hypothalamic neurons | Animal (preclinical) | ,, and [Caputi et al. (2021)] [Cintado et al. (2025)] [Souza et al. (2023)] |
| BDNF | Synaptic plasticity regulation, neuroprotection | Hippocampal/prefrontal TrkB receptors | Human & animal | ,, and [Baranowski et al. (2023)] [Huang et al. (2021)] [Oyovwi et al. (2025)] |
Metabolic-immune cross-regulation mechanisms
Exercise-induced alterations in metabolic state profoundly influence immune cell function. This is especially true in the context of inter-organ communication between peripheral immune cells and the CNS. Systemic metabolic changes during and after exercise modulate immune cell activation. They also affect differentiation and trafficking of these cells. These changes in turn impact neuroimmune interactions (Arner and Rathmell, 2023; Hartmann et al., 2021). Metabolic reprogramming of immune cells is characterized by shifts in glycolytic and oxidative phosphorylation pathways. This reprogramming is essential for their functional adaptation (Hu et al., 2022). Exercise induces a metabolic milieu that favors anti-inflammatory immune phenotypes. It promotes the release of anti-inflammatory cytokines such as interleukin-10. This cytokine can cross the BBB or signal via peripheral nerves to modulate CNS inflammation (Ben-Khemis et al., 2023; Saxton et al., 2021; Yang et al., 2022).
Furthermore, exercise-induced metabolic adaptations facilitate peripheral immune signal communication to the CNS. For example, metabolites such as lactate and ketone bodies influence immune cell metabolism. They also regulate cytokine production by these cells. This shaping of systemic inflammatory responses contributes to neural health (Duraj et al., 2024; Watson et al., 2023). The release of myokines and hepatokines during exercise also modulates immune function. It enhances anti-inflammatory pathways and promotes immune tolerance (Babaei and Yadegari, 2025). This metabolic-immune crosstalk is critical for maintaining CNS homeostasis. It may underlie the beneficial effects of exercise on neuroinflammatory and neurodegenerative conditions. Thus, exercise-induced metabolic shifts act as key regulators of immune cell function. They also modulate immune signaling to the CNS, fostering an anti-inflammatory environment conducive to neural health (Figure 1).
Metabolic-immune crosstalk in the NIM axis: exercise-induced reprogramming. Mechanistic model of exercise-induced metabolic-immune crosstalk in the NIM axis. Upstream, exercise triggers metabolic shifts (lactate elevation, ketone body production, PGC-1α upregulation). These metabolic signals drive immune cell metabolic reprogramming (switch from glycolysis to oxidative phosphorylation) and phenotypic conversion (macrophage M1 → M2 polarization). Consequently, anti-inflammatory cytokines (IL-10) are released, which modulate central neuroinflammation by crossing the blood–brain barrier or via peripheral nerve signaling. NIM, neuro-immuno-metabolic; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha; IL, interleukin; BBB, blood–brain barrier.
Dynamic bidirectional communication of the neuro-metabolic axis
The CNS possesses sophisticated mechanisms to sense peripheral metabolic changes. It also responds to these changes to orchestrate energy distribution and neural activity. This optimization of physiological function occurs during exercise. Central metabolic sensing involves specialized neurons in hypothalamic and brainstem nuclei. These neurons detect circulating nutrients, hormones, and metabolites. They adjust autonomic outputs accordingly (Lin et al., 2025; Ma et al., 2023). Exercise induces temporal and spatial coordination of energy metabolism and neural activity. This ensures cognitive functions are maintained or enhanced. The coordination persists despite increased systemic energy demands (Dang et al., 2024; Lao-Peregrin et al., 2024; Yang et al., 2023). During exercise, the CNS integrates metabolic signals such as glucose, lactate, and ketones. It modulates neuronal excitability and synaptic plasticity. This modulation supports motor and cognitive performance (Dejanovic et al., 2024; Lao-Peregrin et al., 2024). Dynamic changes in cerebral blood flow and substrate utilization facilitate this integration. These changes are tightly regulated to meet fluctuating energy requirements of active neural circuits (Krolak et al., 2025; Oprea et al., 2025). Additionally, the CNS modulates peripheral metabolism through autonomic nervous system outputs. It influences substrate mobilization, insulin sensitivity, and inflammatory status. This creates a feedback loop that sustains metabolic homeostasis (Actis Dato et al., 2024; Tucci et al., 2021; Wan et al., 2025). The temporal coordination of metabolic and neural responses during exercise is critical for optimizing cognitive outcomes. Evidence indicates that metabolic flexibility and efficient substrate switching underpin enhanced cognitive resilience (Ang et al., 2025; Grasmann et al., 2021; Tsilingiris et al., 2021). This bidirectional neuro-metabolic communication axis exemplifies integrated physiological adaptations to exercise (Table 2).
| Signaling pathway | Core molecular components | Main biological functions | Primary evidence source | References |
|---|---|---|---|---|
| PGC-1α/FNDC5/irisin/BDNF | PGC-1α, FNDC5, irisin, BDNF | Metabolic-neural cross-talk; promote neurogenesis, synaptic plasticity | Animal (preclinical) | ,, and [Ali et al. (2024)] [Lee et al. (2025)] [Zalouli et al. (2023)] |
| AMPK-PGC1α-PPARγ | AMPK, PGC1α, PPARγ | Immune cell metabolic reprogramming; induce anti-inflammatory phenotype | Animal (preclinical) | ,, and [Hu et al. (2022)] [Murugathasan et al. (2023)] [Ying et al. (2025)] |
| IL-6-IL-10-microglial polarization | IL-6 (myokine), IL-10, microglia | Initiate repair-oriented inflammation; inhibit neuroinflammation | Animal (preclinical) | ,, and [Liu et al. (2021)] [Mao et al. (2020)] [Yu and Chen (2025)] |
| SCFA-TLR4-cytokine | SCFAs, TLR4, anti-inflammatory cytokines | Protect intestinal barrier; alleviate central neuroinflammation | Animal (preclinical) | ,, and [Caputi et al. (2021)] [Dmytriv et al. (2024)] [Souza et al. (2023)] |
Exercise-induced remodeling of the neuroimmune axis: a paradigm shift from pathological inflammation to reparative programs
Limitations of traditional concepts of neuroinflammation
Traditional views of neuroinflammation have predominantly characterized inflammation as a pathological process. It is detrimental to neural function and often implicated as a primary driver of neurodegenerative diseases and cognitive impairment (Moujalled et al., 2021; Tian et al., 2022). This perspective tends to frame CNS inflammation as a uniform, deleterious response. It leads to neuronal damage and dysfunction. However, such a unidimensional understanding neglects key features of CNS inflammatory processes. These include inherent complexity, diversity, and temporal dynamics (Adamu et al., 2024; Li et al., 2024). In reality, neuroinflammation encompasses a spectrum of responses. These can be harmful or beneficial depending on context, intensity, and activation stage. Current evidence suggests that microglia do not merely switch between binary “M1” (neurotoxic) and “M2” (neuroprotective) states, but rather exist along a dynamic multidimensional spectrum of activation. Depending on the metabolic and environmental context, microglia can adopt specific transcriptional signatures that range from pro-inflammatory surveillance to repair-oriented functional states. These states are temporally regulated to support tissue remodeling and synaptic plasticity rather than simply suppressing inflammation (Faust et al., 2025; Guo et al., 2022; Wang et al., 2021; Yu et al., 2023). Exercise-induced inflammatory responses exemplify this duality. Unlike pathological inflammation linked to chronic neurodegeneration, exercise triggers a transient regulated inflammatory milieu. This milieu promotes neuroprotection and repair. Acute exercise bouts induce controlled elevations in cytokines such as interleukin-6 (IL-6). In this context, IL-6 acts as a myokine with systemic anti-inflammatory effects. It does not function as a pro-inflammatory mediator (Mao et al., 2020; Ren et al., 2020; Zheng et al., 2020). Furthermore, exercise modulates immune cell populations and their activation states. It enhances recruitment and function of regulatory immune cells. These cells mitigate chronic inflammation. This nuanced understanding challenges the traditional inflammation paradigm. It highlights that inflammation is not inherently pathological. Instead, it can be a critical component of CNS homeostasis and recovery (Dikiy and Rudensky, 2023; Rogovskii, 2020). Therefore, distinguishing between pathological and physiological inflammation is essential. Physiological inflammation includes exercise-induced responses (Table 3). This distinction aids in developing targeted interventions. These interventions harness beneficial neuroimmune interactions while mitigating harmful ones (Barad et al., 2023; Su and Su, 2025).
| Characteristic | Pathological inflammation | Repair-oriented inflammation | Primary evidence source | References |
|---|---|---|---|---|
| Immune cell phenotype | Microglial M1 polarization; pro-inflammatory cytokine dominance | Microglial M1 to M2 polarization; Treg recruitment | Animal (preclinical) | ,, and [Guo et al. (2022)] [Mao et al. (2020)] [Wang et al. (2021)] |
| Key molecules | Increased TNF-α, IL-1β; pro-inflammatory chemokines | Increased IL-6 (myokine), IL-10, BDNF; reduced pro-inflammatory cytokines | Animal (preclinical) | ,, and [Liu et al. (2021)] [Murugathasan et al. (2023)] [Yu and Chen (2025)] |
| Neural effects | Synaptic damage, neuronal dysfunction; cognitive decline | Synaptic remodeling, neurogenesis; neuronal protection, debris clearance | Animal (preclinical) | ,, and [Nicastri et al. (2022)] [Yu and Chen (2025)] [Zalouli et al. (2023)] |
| Molecular mechanism | Sustained NF-κB activation; oxidative stress, mitochondrial DNA release | AMPK-PGC1α-PPARγ activation; enhanced mitochondrial function | Animal (preclinical) | ,, and [Hu et al. (2025)] [Liu et al. (2024)] [Ying et al. (2025)] |
Exercise-induced reparative inflammatory mechanisms
Exercise initiates a complex reparative inflammatory cascade. This cascade orchestrates systemic and central immune responses. These responses are conducive to neural repair and cognitive enhancement. A pivotal mediator in this process is interleukin-6 (IL-6). It is released from contracting skeletal muscles during exercise. IL-6 exhibits a dual role. It acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine (Liu et al., 2024; Raut and Cucullo, 2025; Stojanovic et al., 2025). Exercise-induced IL-6 elevation transiently stimulates anti-inflammatory pathways. This includes upregulation of interleukin-10 (IL-10). IL-10 is an anti-inflammatory cytokine. It plays a critical role in modulating microglial activation. It also promotes a reparative phenotype (Illes et al., 2020; Pang et al., 2022; Radin and Tsirka, 2020). IL-10 upregulation in the CNS contributes to microglial remodeling. It shifts microglia from a pro-inflammatory to an anti-inflammatory state. This fosters an environment conducive to neuroprotection and synaptic plasticity. Concurrently, exercise activates neuroprotective programs. These include enhanced antioxidant defenses. They also involve increased expression of neurotrophic factors such as BDNF (Lu et al., 2025; Malange et al., 2022). These neurotrophic factors support neuronal survival. They promote neurogenesis and facilitate synaptic remodeling. Collectively, these effects underpin cognitive improvements.
Additionally, exercise-induced improvements in mitochondrial function reduce oxidative stress. They also decrease mitochondrial DNA release. Such release can otherwise trigger innate immune activation and neuroinflammation (Benedict and Joshi, 2025; Gong et al., 2024; Zhang et al., 2025). Modulation of mitochondrial quality and metabolic pathways in immune cells further tempers inflammatory responses. Macrophages are a key example of such immune cells. This modulation supports tissue repair. This multifaceted reparative inflammatory mechanism underscores a key synergy. Exercise-induced cytokine signaling and metabolic adaptations work together. They remodel the CNS immune landscape. This shift moves from chronic inflammation to a state favoring repair and resilience (Barad et al., 2023; Seo et al., 2019; Wen et al., 2025) (Figure 2).
Exercise-induced resolving inflammation: a neuroprotective cascade. Schematic of the exercise-induced reparative inflammatory cascade. Skeletal muscle contraction during exercise releases IL-6 as a myokine, initiating a sequential anti-inflammatory program: IL-6 upregulates IL-10 expression, which drives microglial phenotypic shifts from a pro-inflammatory state toward a resolving, reparative phenotype (characterized by upregulation of markers such as CD206 and TGF-, and metabolic reprogramming toward oxidative phosphorylation). IL, interleukin; M1, classically activated macrophage phenotype; M2, alternatively activated macrophage phenotype; TGF-β, transforming growth factor beta; BDNF, brain-derived neurotrophic factor. β
Dynamic regulation of immune cell subtypes and neural function by exercise
Exercise induces dynamic alterations in immune cell subtypes. These changes occur both in the periphery and within the CNS. They critically influence neural plasticity and function. Within the CNS, microglia are the resident immune cells. They undergo exercise-induced phenotypic shifts. These shifts are characterized by reduced pro-inflammatory markers. They also involve increased anti-inflammatory and neuroprotective profiles (Chen et al., 2023; Ronaldson and Davis, 2020; Zhang et al., 2021). This functional shift towards a reparative phenotype enhances microglial capacities. These include debris clearance, secretion of neurotrophic factors, and support of synaptic remodeling. These capacities facilitate neuroplasticity and cognitive resilience. Peripheral immune cells also participate in this dynamic regulation. Exercise promotes mobilization and trafficking of lymphocytes. Regulatory T cells (Tregs) are a key subset of these lymphocytes. They can infiltrate the CNS and modulate local immune environments (Deng et al., 2023; Qu et al., 2024; Zhang et al., 2025). Crosstalk between peripheral immune cells and CNS-resident cells is further influenced by exercise. It alters blood–brain barrier permeability and chemokine expression. These alterations regulate immune cell migration (Hu et al., 2025).
Notably, recruitment of regulatory immune subsets helps suppress chronic neuroinflammation. It also supports repair processes. Moreover, exercise modulates the balance of immune cell subpopulations. It increases naïve T cells and reduces senescent or exhausted phenotypes. This is particularly relevant in aging populations. Immune senescence in these populations contributes to neurodegenerative risk. These immune cell dynamics link to key cellular improvements. They are associated with enhanced mitochondrial function. They also involve metabolic reprogramming within immune cells. These changes further boost their reparative capacities (Lewis et al., 2025; Rocamora-Reverte et al., 2022; Yin et al., 2025). Collectively, exercise-induced remodeling of immune cell subtypes is pivotal. Their interactions with neural cells form a key mechanism. This mechanism provides a plausible pathway by which physical activity promotes CNS repair, supporting cognitive enhancement and psychological resilience (Mu et al., 2025; Papp et al., 2021; Wang et al., 2022). However, the precise molecular signatures characterizing these immune shifts remain to be fully mapped, underscoring the need for advanced single-cell sequencing approaches.
Exercise as a modulator of the muscle-gut-brain axis: neuroimmune integration via the microbiome and metabolites
Gut microbiota composition and exercise-related changes
Exercise is increasingly recognized as a key modulator of gut microbiota composition, diversity, and abundance. These microbial changes in turn influence systemic health and brain function. Regular physical activity promotes increased microbial diversity. It also fosters the proliferation of beneficial bacterial taxa, particularly those within the Firmicutes phylum. This phylum is often linked to positive health outcomes (Dalton et al., 2019). Studies in humans and animal models have yielded consistent findings. Endurance and moderate-intensity aerobic exercise enhance the relative abundance of genera such as Bifidobacterium, Blautia, and Phascolarctobacterium. These bacteria contribute to improved metabolic and immune functions (Aragón-Vela et al., 2021; Yang et al., 2021). Conversely, sedentary lifestyles correlate with reduced microbial diversity and dysbiosis. These conditions are associated with metabolic and neuropsychiatric disorders. Exercise-induced shifts in gut microbiota vary across exercise modalities. For example, cardiorespiratory exercise induces transient alterations in microbiome composition. Resistance training may exert minimal effects on microbial structure (Bycura et al., 2021).
Beyond compositional changes, exercise influences the functional capacity of the microbiome. It enhances pathways related to short-chain fatty acid (SCFA) metabolism and amino acid catabolism. These pathways are critical for host energy homeostasis and immune regulation (Chen See et al., 2022; Greenhill, 2020). Importantly, exercise modulates intestinal barrier integrity. Evidence includes increased expression of tight junction proteins such as ZO-1, Occludin, and Claudin-1. This upregulation reduces intestinal permeability and systemic endotoxemia (Santos et al., 2024; Segui-Perez et al., 2024; Yu et al., 2017). Improved gut barrier function mitigates chronic low-grade inflammation. Such inflammation can adversely affect brain health. Moreover, exercise-induced microbial changes influence systemic immune status. They modulate pro- and anti-inflammatory cytokine profiles, contributing to a balanced immune response (Quaresma et al., 2024). Collectively, these findings underscore that exercise reshapes the gut microbiota ecosystem. It enhances microbial diversity, promotes beneficial bacteria, and strengthens gut barrier function. These adaptations together support systemic immune homeostasis. They potentially mediate exercise-induced cognitive and psychological benefits (Table 4).
| Dominant microbiota | Core metabolites | Neural effects | Primary evidence source | References |
|---|---|---|---|---|
| Firmicutes phylum | Short-chain fatty acids (SCFAs) | Promote neurogenesis; increase BDNF, inhibit neuroinflammation | Human & animal | ,, and [Aragón-Vela et al. (2021)] [Cintado et al. (2025)] [Quaresma et al. (2024)] |
| Bifidobacterium genus | Acetate, propionate, tryptophan metabolites | Regulate emotion; anxiolytic effect, modulate CNS serotonin | Animal (preclinical) | ,, and [Dalton et al. (2019)] [Molska et al. (2024)] [Yang et al. (2021)] |
| Blautia genus | Butyrate, amino acid derivatives | Enhance cognitive flexibility; consolidate memory | Human (observational) & animal | ,, and [Aragón-Vela et al. (2021)] [Bycura et al. (2021)] [Okamoto et al. (2019)] |
| Phascolarctobacterium genus | SCFAs, 3-Hydroxyphenylacetic acid | Enhance stress resistance, psychological resilience | Animal (preclinical) | ,, and [Chen See et al. (2022)] [Greenhill (2020)] [Yang et al. (2021)] |
Role of microbial metabolites in the neuro-immune-metabolic axis
Microbial metabolites, particularly short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate, act as crucial mediators. They link the gut microbiota to the central nervous system (CNS) via the neuro-immune-metabolic axis. These SCFAs are produced through gut bacterial fermentation of dietary fibers. They exert systemic effects extending to brain function and immune modulation (Erny et al., 2021; Hays et al., 2024; Portincasa et al., 2022). SCFAs influence brain health through multiple specific mechanisms. They can cross the blood–brain barrier or signal via the vagus nerve. This modulation affects neuroinflammation, neuroplasticity, and neurotransmitter synthesis (Caputi et al., 2021; Shin et al., 2019). For instance, butyrate functions as a histone deacetylase inhibitor. It promotes gene expression that supports neurogenesis and synaptic plasticity. These processes are essential for cognitive function and mood regulation. Additionally, SCFAs regulate central immune cells such as microglia. They attenuate microglial activation and reduce neuroinflammation. Neuroinflammation is a key factor in neurodegenerative and psychiatric disorders (Zhang et al., 2022).
Beyond SCFAs, other microbial metabolites have notable effects. Compounds like 3-Hydroxyphenylacetic acid and 4-Hydroxybenzoic acid confer cardioprotective effects post-myocardial infarction. This highlights the systemic reach of microbial metabolites (Zhou et al., 2022). Crucially, the gut microbiota metabolizes dietary tryptophan into indole and its derivatives (indole-3-propionic acid). These metabolites function as endogenous agonists for the aryl hydrocarbon receptor (AhR) on astrocytes and microglia. Activation of AhR signaling promotes the differentiation of regulatory T cells (Tregs) and suppresses neuroinflammation, thereby linking gut microbial metabolism directly to CNS immune tolerance and providing a complementary pathway to SCFAs for neuroprotection (Kiran et al., 2025). The interplay between microbial metabolites and host immune signaling pathways further integrates gut-derived signals. Key pathways include TLR4 and cytokine cascades. These interactions shape systemic immune responses that impact brain function (Dmytriv et al., 2024; Jing et al., 2025). Notably, exercise enhances SCFA production by promoting SCFA-producing bacteria. This amplification strengthens neuro-immune-metabolic effects. It contributes to improved exercise capacity, metabolic efficiency, and psychological resilience. Therefore, microbial metabolites act as pivotal biochemical messengers within the neuro-immune-metabolic axis, likely serving as key mediators of the beneficial effects of exercise on brain health and systemic immunity (Qiao et al., 2025; Zhao et al., 2025) (Figure 3).
Microbial metabolites as messengers in the gut-brain axis: exercise-modulated pathways. Mechanisms of microbial metabolites mediating gut-brain communication in exercise. Left, exercise remodels gut microbiota (enrichment of Firmicutes phylum, Bifidobacterium genus, etc.) to enhance production of short-chain fatty acids (SCFAs: acetate, propionate, butyrate) and secondary metabolites (tryptophan metabolites). Middle, SCFAs transmit signals to the central nervous system (CNS) via two pathways: direct penetration of the blood–brain barrier (BBB) and indirect signaling through the vagus nerve. Right, these metabolites exert central effects including inhibiting microglial activation, upregulating BDNF expression, promoting neurogenesis in the hippocampal dentate gyrus, and modulating neurotransmitter (serotonin) synthesis. All adaptations converge to improve brain health. SCFA, short-chain fatty acid; CNS, central nervous system; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor.
Integrative perspective of the gut-brain and muscle-brain axes
The gut-brain axis and muscle-brain axis are interconnected communication networks. They collectively form a comprehensive neuro-immune-metabolic framework. This framework mediates exercise-induced benefits on brain function and psychological resilience. The gut-brain axis involves bidirectional signaling between the gastrointestinal tract and the CNS. Neural pathways such as the vagus nerve, endocrine, immune, and metabolic routes mediate this communication. The gut microbiota plays a central role in this axis (Thaiss, 2023; Xia and Huang, 2025). Concurrently, skeletal muscle functions as an endocrine organ. It secretes myokines and exerkines such as irisin and BDNF. These factors influence neuroplasticity, neurogenesis, and systemic immune responses (Cutuli et al., 2023; Saponaro et al., 2024). Exercise modulates both axes synergistically. It remodels gut microbiota composition and function. This enhancement increases production of metabolites like SCFAs that influence muscle metabolism and brain function. Meanwhile, muscle-derived factors reciprocally affect gut physiology and microbiota composition (Scriven et al., 2023; Yin et al., 2022).
This bidirectional crosstalk establishes a muscle-gut-brain network. It integrates metabolic, immune, and neuroendocrine signals to optimize cognitive performance and psychological well-being (Cammisuli et al., 2022). For example, exercise-induced increases in irisin promote hippocampal BDNF expression. This supports cognitive enhancement. Gut microbiota-derived metabolites modulate systemic inflammation and neurotransmitter systems. These systems are involved in mood regulation (Molska et al., 2024). Furthermore, the gut microbiome influences exercise motivation. It acts through endocannabinoid-mediated pathways that enhance dopaminergic signaling in the brain. This illustrates a microbiome-dependent gut-brain-muscle interaction (Dohnalová et al., 2022; Sun et al., 2023). The integration of these axes also involves immune modulation. Exercise-induced changes in gut and muscle secretions regulate central and peripheral immune cells. This contributes to neuroprotection and stress resilience (Cammisuli et al., 2022; Schlegel et al., 2019). Collectively, the gut-brain and muscle-brain axes coalesce into a unified neuro-immune-metabolic network. Exercise-induced modulation of gut microbiota and muscle-derived factors orchestrates systemic and central adaptations. These adaptations enhance brain function and psychological resilience. This integrative perspective underscores the therapeutic potential of targeting the muscle-gut-brain axis. It aims to optimize cognitive health and mental well-being (Bower and Kuhlman, 2023) (Figure 4).
Muscle-gut-brain axis: bidirectional communication in exercise-induced brain health. Schematic of the muscle-gut-brain axis’s triangular bidirectional network. It comprises three core axes (muscle/gut/brain) with key signaling paths and inter-axis crosstalk, ultimately boosting cognitive enhancement and psychological resilience, visualizing the NIM axis’s integrative interactions. NIM, neuro-immuno-metabolic.
Conclusions and perspectives
In conclusion, this review has systematically constructed a unified framework of the neuro-immune-metabolic (NIM) axis. It marks a notable advancement beyond traditional isolated mechanistic views. Exercise serves as a dynamic energy challenge that integrates neural, immune, and metabolic systems, clarifying how physical activity enhances cognitive function and psychological resilience. This holistic approach underscores the need to move beyond siloed research paradigms, helping to appreciate the complex bidirectional interactions underpinning exercise-induced neurobiological benefits.
Notably, the NIM axis presented in this review is distinct from existing frameworks. While models such as the muscle-brain axis, gut-brain axis, psychoneuroimmunology, and immunometabolism have independently elucidated key bidirectional pathways, they often examine physiological interactions in isolation or focus primarily on pathological states. The NIM axis represents a fundamental shift towards a unified, tri-directional regulatory network. Unlike psychoneuroimmunology, which traditionally emphasizes stress-induced immune modulation, or immunometabolism, which focuses on cellular energetics, this framework positions physical exercise as a systemic “energy challenge” that forces a recalibration across all three systems simultaneously. Its distinctive novelty lies in the identification of “repair-oriented inflammation” as the central integrator—where metabolic signals (e.g., lactate, ketones) act as the trigger to switch immune phenotypes from pathological to reparative, directly driving neural plasticity. Thus, the NIM axis offers a mechanistic explanation for how metabolic stress is transduced into psychological resilience, a dynamic often overlooked in linear bipartite models.
A particularly transformative insight discussed herein is the concept of exercise-induced “resolving inflammation.” It challenges the long-standing dogma that inflammation is solely detrimental in the nervous system. Instead, this review highlights inflammation’s dual nature, emphasizing its critical role in neuroprotection and repair. This nuanced understanding prompts a reevaluation of neuroinflammatory processes in the context of exercise and neurological health, suggesting controlled inflammatory responses may be harnessed therapeutically to promote brain resilience and recovery.
Furthermore, the deep integration of the gut-brain and muscle-brain axes within the NIM framework reveals key insights. It identifies the microbiome and its metabolites as central players in exercise neurobiology. This intersection not only broadens the scope of exercise neuroscience but also bridges metabolic and immune pathways with neural function, positioning the microbiota as a pivotal mediator of exercise’s systemic effects. Such insights encourage a multidisciplinary research approach that combines microbiology, immunology, metabolism, and neuroscience to unravel complex crosstalk.
Notably, this review delineates the mechanistic specificity of different exercise modalities, clarifying how they activate the NIM axis (Table 5) and lay a solid theoretical foundation for precision exercise medicine. Recognizing that specific exercise modalities elicit distinct neuro-immune-metabolic responses enables tailored interventions aimed at optimizing cognitive and mental health outcomes. This precision approach holds promise for addressing heterogeneity in exercise responsiveness, particularly for individuals who show minimal or no benefit from conventional exercise regimens.
Looking forward, advancing this field will require leveraging cutting-edge technologies. Key examples include multi-omics, single-cell sequencing, and advanced neuroimaging. These tools will be indispensable for dissecting intricate cellular and molecular mechanisms that drive exercise-induced neuroplasticity and immune modulation. Furthermore, they will facilitate the development of mechanism-driven individualized exercise interventions that can overcome the challenge of non-responders and maximize therapeutic efficacy (Wang et al., 2024; Zhou et al., 2025).
Additionally, future studies must account for confounding lifestyle variables. Factors such as diet, sleep quality, and stress management likely interact with exercise to synergistically or antagonistically modulate the NIM axis.
In synthesizing diverse research perspectives and findings, this review advocates for a balanced integrative research paradigm. It appreciates both the complexity and specificity of exercise-induced neuro-immune-metabolic interactions. The convergence of these systems not only enriches our understanding of exercise neuroscience but also opens new avenues for clinical translation. Ultimately, this unified NIM axis framework heralds a new era in exercise neurobiology, promising to revolutionize how we harness physical activity to enhance brain health and psychological resilience across the lifespan.
| Exercise modality | Primary metabolic/immune mediators | Key neural mechanisms | Cognitive & mental health outcomes | Primary evidence source | References |
|---|---|---|---|---|---|
| Aerobic training (AT) | PGC-1α, Irisin, VEGF, BDNF (chronic elevation) | Hippocampal neurogenesis; Increased cerebral blood flow; Synaptic angiogenesis | Enhanced memory and learning; Reduced depression/anxiety; Increased gray matter volume | Human RCTs & animal models | ,, and [Antunes et al. (2020)] [Balbim et al. (2024)] [Enette et al. (2020)] |
| Resistance training (RT) | IGF-1, Myostatin inhibition, IL-6 (myokine), Lactate (moderate) | White matter integrity (myelination); Frontal lobe activation; Functional connectivity | Improved executive function; Attention control; Reduced cognitive frailty | Human RCTs (limited animal data) | and [Balbim et al. (2024)] [Herbert et al. (2020)] |
| High-intensity interval training (HIIT) | Lactate (high surge), Ketone bodies, BDNF (acute spike), Catecholamines | Cortical excitability; “Energy challenge” induced plasticity; Rapid metabolic reprogramming | Cognitive flexibility; Inhibitory control; Rapid mood elevation | Human RCTs & animal models | and [Dos Santos et al. (2020)] [Waddington et al. (2024)] |
Acknowledgments
We extend our gratitude to all authors for their dedication and contributions.
Funding Statement
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Basic Scientific Research Operating Expenses Project for Provincial Undergraduate Universities of Heilongjiang Province (Grant No. 2024KYYWF-TD06) and the Basic Scientific Research Operating Expenses Project for Provincial Undergraduate Universities of Heilongjiang Province (Grant No. 2025KYYWF-TD07).
Footnotes
Author contributions
YS: Conceptualization, Investigation, Methodology, Software, Supervision, Writing – original draft, Writing – review & editing. ZM: Conceptualization, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing. YY: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. HC: Conceptualization, Writing – original draft, Writing – review & editing. HW: Writing – original draft, Writing – review & editing. XC: Writing – original draft, Writing – review & editing. WZ: Writing – original draft, Writing – review & editing. JL: Conceptualization, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Writing – original draft, Writing – review & editing. CW: Funding acquisition, Project administration, Investigation, Resources, Writing – review & editing, Supervision.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Gut-Brain Axis