Major depressive disorder (MDD) is a significant global health concern, affecting 4-5% of the world's population. Characterized by persistent depressed mood or anhedonia alongside cognitive and somatic symptoms, MDD significantly impacts individuals' lives, increasing suicidality risk and the likelihood of developing physical comorbidities. The pathophysiology of MDD is complex and multifactorial, involving genetic and epigenetic alterations, neuroendocrine and immune dysregulation, neuroplasticity impairments, and importantly, disruptions in the microbiota-gut-brain axis. The hypothalamic-pituitary-adrenal (HPA) axis, crucial for stress response regulation, is often dysfunctional in MDD, potentially influencing gut microbiota composition and increasing gastrointestinal permeability. Inflammation plays a key role, with elevated serum inflammatory markers in MDD patients. Lipopolysaccharide (LPS) studies in animal models highlight the link between peripheral inflammation, blood-brain barrier disruption, microglial activation, neuroinflammation, and depressive-like behaviors. The tryptophan (Trp)-kynurenine metabolic pathway is also implicated, with an inflammatory shift favoring neurotoxic over neuroprotective metabolites. While pharmacological interventions are common, lifestyle modifications, including physical exercise, offer significant antidepressant effects, particularly for mild MDD, warranting further investigation into their mechanisms, especially concerning gut microbiota modulation.

The literature review extensively covers the established links between MDD and inflammation, the gut-brain axis, and the role of the gut microbiota. Studies demonstrating altered microbiota composition (dysbiosis) in MDD patients are reviewed, along with preclinical research showing the potential of probiotics to improve depression-like phenotypes. The role of the vagus nerve in gut-brain communication, and the impact of gut microbiota-derived metabolites like short-chain fatty acids (SCFAs) and lactate on brain function and inflammation are discussed. SCFAs, particularly butyrate, are highlighted for their role in maintaining intestinal barrier integrity, modulating inflammation, and influencing neurotrophic factors. The kynurenine pathway is discussed in relation to gut microbiota-mediated inflammation and Trp metabolism. Existing literature on the benefits of physical exercise for MDD and its effects on cognitive function are also reviewed.

This is a narrative review article. The authors conducted a comprehensive literature search across various databases (specific databases not listed) to identify relevant research on the relationship between physical exercise, gut microbiota, and major depressive disorder. The search terms included “gut microbiota,” “major depressive disorder,” and “physical exercise,” combined with relevant keywords pertaining to inflammation, the gut-brain axis, metabolites (SCFAs, lactate, kynurenine), neurotrophic factors (BDNF, IGF-1, VEGF), and myokines (irisin, cathepsin B, IL-6). The selected studies included both human and animal studies focusing on preclinical models, clinical trials, and observational studies. The articles were then analyzed to extract relevant data and synthesize current knowledge. There is no mention of specific inclusion/exclusion criteria or a systematic review process beyond the broad literature search. The authors present information from different studies narratively, without performing meta-analysis or quantitative synthesis of data.

The review finds strong evidence supporting a link between gut dysbiosis and MDD. Physical exercise appears to exert its antidepressant effects, at least in part, via modulation of the gut microbiota and the gut-brain axis. Key mechanisms identified include: 1) **Increased SCFA production**: Physical exercise increases the production of SCFAs, particularly butyrate, leading to improved gut barrier integrity and reduced inflammation. Butyrate, through GPR109A activation, inhibits the NLRP3 inflammasome and pro-inflammatory pathways and regulates gene expression. 2) **Myokine production**: Exercise stimulates myokine production, such as irisin and cathepsin B, which can cross the blood-brain barrier and influence brain function. Irisin may increase BDNF levels, promoting neurogenesis and synaptic plasticity, while cathepsin B exhibits pro-neuroplasticity effects. 3) **Lactate metabolism**: Lactate, produced during exercise and by the gut microbiota, can cross the blood-brain barrier and stimulate the expression of synaptic plasticity-related genes, inhibit the NLRP3 inflammasome, and potentially increase BDNF. 4) **Neurotrophic factor regulation**: Exercise increases the levels of neurotrophic factors like BDNF, IGF-1, and VEGF, promoting neurogenesis and synaptogenesis. 5) **Kynurenine pathway modulation**: Exercise may increase the expression of kynurenine aminotransferase (KAT), promoting the peripheral conversion of KYN to KYNA. This reduces circulating KYN, preventing its accumulation in the brain and mitigating its neurotoxic effects. 6) **Endocannabinoid system activation**: Exercise activates the endocannabinoid system, which has been linked to mood regulation. 7) **Anti-inflammatory and antioxidant effects**: Exercise reduces inflammation and increases antioxidant defenses, both peripherally and centrally. 8) **Gut microbiota modulation**: Exercise improves gut microbial diversity and abundance of beneficial bacteria involved in SCFA production, such as Akkermansia muciniphila, Faecalibacterium prausnitzii, and Lactobacillus. Additionally, physical exercise decreases some pathogenic bacteria. 9) **Extracellular vesicles**: Exercise-induced changes in miRNA profiles within extracellular vesicles may play a role in mediating beneficial effects on both gut and brain.

The findings of this review strongly support the hypothesis that physical exercise can effectively alleviate depressive symptoms, at least in part, by modulating the gut microbiota and the gut-brain axis. The multiple mechanisms identified – from increased SCFA production and myokine release to modulation of the kynurenine pathway and anti-inflammatory actions – highlight the complexity and multi-faceted nature of exercise's impact on MDD. The interconnectedness of these mechanisms underscores the importance of considering the gut-brain axis in developing comprehensive therapeutic approaches to MDD. The significant overlap between the effects of exercise and those of antidepressant medications suggests that exercise may serve as a valuable complementary therapy or even a primary intervention for mild to moderate MDD.

Regular physical exercise offers a promising non-invasive strategy for managing MDD by modulating the gut microbiota and influencing the gut-brain axis. Future research should focus on elucidating the specific mechanisms involved, optimizing exercise protocols, and exploring the potential of combining exercise with nutritional interventions to maximize beneficial effects. Further investigation into the role of exercise on the endocannabinoid system and the specific miRNAs within EVs is warranted.

The review acknowledges that several factors can influence the gut microbiota's composition and diversity. The effects of exercise may be influenced by diet, stress, and exercise protocols (intensity, frequency, and duration). Very intense or prolonged exercise may have detrimental effects on gut microbiota and intestinal permeability. Inconsistent methodologies for analyzing gut microbiota composition across different studies may lead to incomparable results. Future research should address these confounding factors to better understand exercise's influence on the gut microbiota and its consequences on brain health.