Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise

The review addresses how dysfunction of the microbiota–gut–brain axis contributes to major depressive disorder (MDD) and evaluates physical exercise as a non-invasive strategy to modulate this axis. MDD is characterized by persistent depressive episodes accompanied by neurocognitive and neurovegetative symptoms and affects 4–5% of the global population. Pathophysiology involves HPA axis dysregulation, systemic and neuroinflammation, microglial activation, impaired neuroplasticity/neurogenesis, and a shift in tryptophan–kynurenine metabolism toward neurotoxic metabolites (e.g., quinolinic acid). Stress and inflammation can increase gut permeability and alter microbial composition, facilitating endotoxin (LPS) translocation and further neuroinflammation. The purpose of the review is to synthesize evidence linking gut dysbiosis to MDD and to examine mechanisms by which physical exercise may beneficially remodel the gut microbiota, attenuate inflammation, enhance neuroplasticity, and improve depressive symptoms.

Gut Microbiota and MDD: The gut hosts ~10^14 microorganisms interacting bidirectionally with the CNS via neural (vagus), endocrine, immune, and metabolic routes (microbiota–gut–brain axis). Environmental factors (diet, antibiotics, stress) perturb this axis and have been associated with MDD. Clinical meta-analyses report altered microbiota in MDD, including increased Bacteroidetes/Firmicutes ratio, decreased Veillonellaceae, Prevotellaceae, Sutterellaceae, and genera Coprococcus, Faecalibacterium, Ruminococcus, Bifidobacterium, Escherichia, with increases in Actinomycetaceae and Paraprevotella. Preclinical studies show probiotic strains (e.g., Bifidobacterium longum infantis CCFM687; Akkermansia muciniphila) ameliorate depressive-like behaviors, modulate HPA axis, BDNF, and neurotransmitters. The vagus nerve mediates gut–brain signaling; vagotomy abolishes LPS-induced depressive-like behaviors in rodents. Microbial metabolites such as SCFAs (acetate, propionate, butyrate) support intestinal barrier, modulate immune responses (NF-κB inhibition, HDAC inhibition), and microglial homeostasis via GPCRs (GPR41/43/109A). Butyrate (GPR109A agonist) reduces pro-inflammatory cytokines, inhibits NLRP3, activates AMPK/SIRT1/Nrf2, and increases neurotrophins (BDNF, VEGF). SCFAs cross the BBB, regulate neuroplasticity and HPA axis, and sodium butyrate exerts antidepressant- and pro-neurogenic effects in animal models. Microbiota-derived lactate also crosses the BBB, fuels neurons, enhances synaptic plasticity and neurogenesis, and shows antidepressant-like effects via HDAC modulation, NMDA–ERK signaling, histone lactylation, and NLRP3 inhibition (HCAR1/β-Arrestin 2). The microbiota regulates tryptophan–kynurenine metabolism; dysbiosis and inflammation favor neurotoxic KYN metabolites (3-HK, QUIN). SCFAs reduce intestinal IDO expression and systemic inflammation, shifting KYN pathways. FMT from MDD patients to rodents induces anhedonia/anxiety-like behaviors, reduces diversity, and elevates KYN/Trp ratio. Physical Exercise, Brain Function and MDD: Exercise (especially aerobic) reduces depression risk and symptoms, with effects comparable to antidepressants and benefits on cognition and hippocampal/white matter integrity. Exercise augments myokines (irisin from FNDC5, cathepsin B), growth factors (BDNF, IGF-1, VEGF), and activates hormetic antioxidant (Nrf2) and anti-inflammatory pathways. Irisin crosses the BBB, increases hippocampal BDNF via PGC-1α–FNDC5, and produces antidepressant-like and pro-neurogenic effects. Cathepsin B promotes neurogenesis/BDNF expression and correlates with fitness/memory. IGF-1 and VEGF mediate neurogenesis, angiogenesis, and antidepressant-like effects; lactate produced during exercise activates HCAR1 to induce VEGF in brain. Exercise modulates inflammatory signaling (reduces IL-1β, TNF-α, TLR4/MyD88/NF-κB; increases IL-10, miR-223) and impacts the kynurenine pathway by upregulating skeletal muscle KAT (via PGC-1α1–PPARα/δ), converting KYN to KYNA (GPR35 agonist that cannot cross BBB), thereby reducing neurotoxic KYN in brain. The endocannabinoid system (AEA, 2-AG; CB1/CB2) is also activated by exercise and associates with mood regulation. Physical Exercise and Gut Microbiota: Exercise increases SCFAs, particularly butyrate, in rodents and humans, strengthens tight junctions (via AMPK) and reduces circulating LPS. It enhances microbial diversity and enriches butyrate producers (Ruminococcaceae, Lachnospiraceae, Faecalibacterium prausnitzii), Akkermansia muciniphila, and in athletes, taxa like Prevotellaceae and Veillonella (which metabolizes lactate to propionate) linked to performance. Exercise can reduce pathogens (e.g., Clostridium difficile). Gut–muscle crosstalk involves SCFA activation of AMPK, GPR41/43 in muscle, promoting mitochondrial biogenesis and IGF-1 release. Exercise-induced microbiota changes can transfer via FMT, improving hippocampal synaptic markers and GPCR expression in recipients. Irisin itself modulates microbiota and intestinal barrier, reducing endotoxemia and inflammatory cytokines, and irisin deficiency associates with dysbiosis and depressive-like behaviors. Exercise alters microbial amino acid metabolism (Trp, phenylalanine, tyrosine) and influences KYN/KYNA balance; KYNA exerts gut-protective anti-inflammatory actions through GPR35. Microbial extracellular vesicles (notably from A. muciniphila) and exercise-induced EV miRNAs may mediate anti-inflammatory and antioxidant signaling (Nrf2). Combined exercise–nutraceutical interventions (polyphenols, n-3 PUFA, probiotics, vitamin D3) further modulate microbiota, inflammation, and performance.

Narrative review. The authors synthesize preclinical and clinical evidence on MDD, gut microbiota, and physical exercise, integrating mechanistic pathways (inflammation, neuroplasticity, SCFAs, lactate, myokines, kynurenine, endocannabinoids), observational studies, randomized interventions, meta-analyses, and fecal microbiota transplantation findings. No formal systematic search strategy, inclusion/exclusion criteria, or quantitative meta-analysis are described. Figures summarize proposed mechanisms.

• MDD is associated with gut dysbiosis (elevated Bacteroidetes/Firmicutes ratio; reduced SCFA-producing taxa such as Faecalibacterium, Coprococcus, Ruminococcus, Bifidobacterium) and systemic/neuroinflammation, microglial activation, and a KYN shift toward neurotoxic metabolites (e.g., QUIN). FMT from MDD patients induces depressive-like phenotypes and elevated KYN/Trp in rodents.
• Microbial metabolites (SCFAs, especially butyrate) maintain gut and BBB integrity, inhibit NF-κB and NLRP3, activate AMPK/SIRT1/Nrf2, and increase neurotrophins (BDNF, VEGF), contributing to antidepressant-like effects; sodium butyrate increases hippocampal BDNF/NGF/GDNF and reverses depressive-like behaviors in mice.
• Lactate from gut and muscle crosses the BBB, fuels neurons, enhances synaptic plasticity gene expression (Arc, c-Fos, Zif268) via NMDA–ERK signaling, modulates HDAC activity and histone lactylation, inhibits NLRP3 through HCAR1/β-Arrestin 2, and exerts antidepressant-like effects dependent on hippocampal neurogenesis.
• Physical exercise reduces depression risk and symptoms in humans; augments myokines (irisin, cathepsin B) and growth factors (BDNF, IGF-1, VEGF), improves cognition and hippocampal structure, and dampens inflammatory signaling (↓ IL-1β, TNF-α, TLR4/MyD88/NF-κB; ↑ IL-10, miR-223).
• Exercise remodels the gut microbiota, increasing SCFAs (rodents: 5–6 weeks of wheel running; humans: 6 weeks of training), enriching butyrate producers (Ruminococcaceae, Lachnospiraceae, F. prausnitzii) and Akkermansia muciniphila, and reducing C. difficile; athletes show higher SCFAs and taxa linked to performance (Veillonella).
• Exercise activates skeletal muscle KAT via PGC-1α1–PPARα/δ, increasing peripheral KYNA (non-BBB permeable, GPR35 agonist), lowering brain exposure to KYN and its neurotoxic derivatives.
• Exercise engages the endocannabinoid system (↑ AEA, 2-AG; ↑ CB1 density), which relates to mood regulation and motivation for exercise via microbiome-dependent pathways.
• FMT from exercised donors increases fecal SCFAs and improves hippocampal synaptic markers and insulin signaling in sedentary mice; exercise-induced irisin also modulates microbiota and preserves intestinal barrier.
• Combined exercise with nutraceuticals (polyphenols, n-3 PUFAs, probiotics, vitamin D3) shows additive benefits on microbiota composition, inflammation, performance, and potentially mood.

The assembled evidence supports a bidirectional relationship between gut microbiota composition/function and MDD pathophysiology. Gut dysbiosis promotes systemic endotoxemia and neuroinflammation, microglial activation, altered KYN metabolism, and impaired neuroplasticity, all contributing to depressive symptoms. Physical exercise emerges as a multifaceted, non-pharmacologic intervention that favorably reshapes the gut ecosystem (increasing SCFAs, especially butyrate; enriching beneficial taxa like Faecalibacterium and Akkermansia), strengthens gut barrier function, and reduces peripheral LPS and inflammation. Concurrently, exercise-driven systemic signals—myokines (irisin, cathepsin B), growth factors (BDNF, IGF-1, VEGF), lactate, and endocannabinoids—interact with central pathways to enhance neurogenesis, synaptogenesis, angiogenesis, and antioxidant defenses while inhibiting inflammasomes (NLRP3) and NF-κB signaling. Exercise also reprograms peripheral KYN metabolism via skeletal muscle KAT to limit neurotoxic KYN derivatives reaching the brain. These converging mechanisms provide a biologically plausible explanation for exercise’s antidepressant effects and suggest that targeting the microbiota–gut–muscle–brain network may optimize depression management. Translation to clinical practice will require defining exercise dose–response, individual microbiome baselines, and potential synergy with dietary or probiotic interventions.

Physical exercise is a promising non-invasive strategy to modulate the microbiota–gut–brain axis and alleviate MDD-related symptoms. Key mechanisms include increased production of SCFAs (notably butyrate) and lactate, enhancement of neurotrophins (BDNF, IGF-1, VEGF) via myokines (irisin, cathepsin B), anti-inflammatory and antioxidant signaling (Nrf2 activation; NF-κB/NLRP3 inhibition), and re-routing of the kynurenine pathway through skeletal muscle KAT to increase peripheral KYNA and lower neurotoxic KYN metabolites in the brain. Exercise-induced microbiome changes can transfer benefits via FMT in animal models, and combined with targeted nutraceuticals, may yield additive effects. Future research should clarify exercise’s direct effects on gut tryptophan metabolism, delineate its modulation of the endocannabinoid system, characterize EV/miRNA-mediated communication, and standardize exercise protocols to optimize microbiome and mental health outcomes.

As a narrative review, no systematic search or meta-analytic methods were applied. The gut microbiota is highly sensitive to confounders—dietary patterns, stress, medications/antibiotics, and methodological differences in microbiome analysis—complicating comparisons across studies. Exercise variables (intensity, frequency, duration) differ widely; very intense and prolonged exercise may impair gut integrity and increase permeability. Inter-individual variability (e.g., BMI, baseline fitness, age) further influences outcomes. More controlled, longitudinal human studies are needed to define dose–response relationships, disentangle diet–exercise interactions, and assess combined nutraceutical–exercise interventions on microbiota and mood.