The vagus nerve, the tenth and longest cranial nerve, is an essential component of the neural pathway, originating in the medulla oblongata and innervating various visceral organs, including the heart, lungs, spleen, and gut. As the principal parasympathetic fiber, it forms a critical anatomical and functional link between the gut and the brain [22]. Approximately 80% of vagal fibers are afferent, transmitting sensory information from the periphery to the brain, whereas the remaining fibers are predominantly efferent and convey motor output [23, 24]. Vagal signaling is implicated in gastrointestinal, metabolic, and neuropsychiatric processes, including those relevant to depression [23, 24]. Intestinal vagal afferents project to the nucleus tractus solitarius (NTS), relaying visceral information to higher autonomic centers in the brain [24]. These fibers monitor microbial metabolites and transmit signals to the brain, influencing mood and stress levels via neural pathways (Figure 1) [24]. Beyond neural interconnections, a complex interplay exists between the gut microbiota, the immune system, and the CNS. Gut microbes regulate immune homeostasis through their metabolic products [25]. The oral and gastrointestinal mucosa, particularly the mucosa-associated lymphoid tissue (MALT), plays a significant role in microbe–immune interactions. Commensal microorganisms constantly interact with this network to maintain immune stability [25]. Microbial peptides and polysaccharides promote the growth of regulatory T cells (Tregs) and the production of anti-inflammatory cytokines like IL-10, influencing innate lymphoid cell activity [26, 27]. Certain microbes, such as Anaeroplasma species, modulate T follicular helper cells, which subsequently adjust IgA production—the most common mucosal antibody. This bidirectional interaction ensures that microbial composition is influenced by the immune system, and microbial metabolites impact immune cell activities [25]. Peripheral immune cells express receptors for neurotransmitters (dopamine and serotonin), allowing gut-derived neuromodulators to regulate cytokine secretion, migration, and differentiation [25]. Immune activation leads to the production of pro-inflammatory cytokines (e.g., IL-6, TNF-α, IL-1β), which can cross or disrupt the blood-brain barrier (BBB), interfering with neurotransmission, altering neuroplasticity, and thereby contributing to MDD pathophysiology [28]. Furthermore, increased gut permeability allows endotoxins, such as LPS, to enter the circulation, fostering neuroinflammation and depressive symptoms [29–31]. The gut also functions as the largest endocrine organ in the human body, with its endocrine arm of the GBA mediated by enteroendocrine cells (EECs) [32]. EECs release hormones that control intestinal motility, secretion, and neurotransmission. Notably, approximately 90% of the body’s serotonin is produced in the gut by enterochromaffin cells [32]. Gut-derived serotonin stimulates vagal afferent fibers, which relay impulses to the NTS in the brainstem. Serotonergic and noradrenergic projections then extend to higher brain centers, including the hypothalamus, amygdala, and cortex, where they contribute to emotion and cognition [32]. This EEC-vagal loop interacts with the hypothalamic–pituitary–adrenal (HPA) axis, forming a neuroendocrine feedback loop sensitive to environmental stressors [15]. An imbalance in this circuit is a significant contributor to the mood and physiological changes associated with stress in depressive disorders.

Mitochondrial dysfunction has emerged as a key pathophysiological mechanism in MDD. These organelles are fundamental for producing adenosine triphosphate (ATP), which powers critical cellular functions [11]. The brain, with its exceptionally high metabolic rate and limited glucose storage capacity, relies heavily on continuous mitochondrial ATP production through oxidative phosphorylation to sustain neuronal function [44]. In MDD, mitochondrial oxidative phosphorylation is frequently impaired, leading to reduced ATP levels, synaptic dysfunction, and increased neuronal vulnerability [45–47]. Consistent findings in postmortem human brain tissue and MDD animal models reveal structural abnormalities of mitochondria and ATP depletion, which contribute to impaired neurotransmitter release and loss of synaptic plasticity [14, 48, 49]. Furthermore, impaired mitochondrial trafficking and localization at synapses may exacerbate energy imbalance and compromise the stability of neural circuits [45]. A primary driver of mitochondrial pathology in MDD is oxidative stress and inflammation. Excessive production of ROS can damage mitochondrial DNA (mtDNA), which lacks the protective histones of nuclear DNA, leading to mutagenesis, defective transcription, and a vicious cycle of oxidative stress [47]. Damaged mtDNA can also be released as damage-associated molecular patterns (DAMPs), activating inflammatory pathways, including NF-κB-related signaling [47, 50]. Chronic neuroinflammation, in turn, impairs energy metabolism, exacerbates purine imbalance, and worsens depressive pathology [51].

Beyond energy impairment, mitochondrial dysfunction plays a crucial role in apoptotic signaling and neuronal death. Overproduction of ROS and depolarization of the mitochondrial membrane can open the mitochondrial permeability transition pore, leading to the release of cytochrome c and the initiation of apoptosis [52, 53]. N-methyl-D-aspartate receptor (NMDAR) overactivation can promote calcium overload, aggravate mitochondrial dysfunction, disrupt mitochondrial membrane potential, and facilitate cytochrome c release into the cytosol [54, 55]. Subsequent activation of caspases triggers neuronal cell death, contributing to synaptic loss and the manifestation of depressive symptoms [56].

Recent literature also indicates that dysregulation of mitochondrial dynamics—fusion, fission, and mitophagy—may contribute to depressive phenotypes [14, 48]. Impaired mitochondrial turnover can promote the accumulation of damaged organelles, reduced ATP generation, and inflammatory signaling, but most mechanistic data derive from preclinical models rather than direct human brain measurements. Emerging peripheral biomarker studies provide more concrete, although still preliminary, human evidence. In a relatively large peripheral blood mononuclear cell analysis, patients with MDD showed increased expression of ER-stress genes (XBP1u, XBP1s, and ATF4) and the mitochondrial biogenesis-related gene MFN2 after adjustment for age, sex, BMI, and medication status, while ASC and MFN2 expression correlated positively with C-reactive protein [57–59]. These findings are important because they move the field beyond generic oxidative-stress narratives toward assayable signatures of organelle stress, inflammasome activation, and mitochondrial remodeling. However, these biomarkers remain peripheral rather than brain-specific, are largely cross-sectional, and have not yet been standardized for diagnosis, prognosis, or treatment stratification. Collectively, the available data support mitochondrial dysfunction as a plausible contributor to MDD pathophysiology, but not as a singular or universally dominant mechanism (Table 1).

Building upon the understanding of mitochondrial dysfunction as a core mechanism in MDD, this section explores the profound influence of the gut microbiota on mitochondrial activity. The gut microbiota exerts a tremendous impact on brain physiology and mitochondrial function via the GBA, controlling neural energy metabolism, oxidative homeostasis, and inflammation [60, 61]. This regulation is mediated by microbial metabolites, signaling molecules, and host-microbe interactions that collectively modulate mitochondrial gene expression and bioenergetic capacity.

Probiotics, especially strains within Lactobacillus and Bifidobacterium, are the most clinically advanced microbiota-targeted interventions. Proposed mechanisms include modulation of gut permeability, inflammatory tone, neurotransmitter precursors, and redox balance [8]. However, clinical results are inconsistent. Positive findings have been reported in some adjunctive trials, whereas other placebo-controlled studies have failed to show significant between-group effects [82–84]. These discrepancies likely reflect heterogeneity in strain composition, baseline diet, concomitant antidepressant use, illness severity, treatment duration, and outcome measures. Therefore, psychobiotics should currently be framed as promising but not yet established adjuncts for MDD. A conceptual overview of probiotic-mediated effects on mitochondrial biogenesis, oxidative stress, inflammatory signaling, and depressive phenotypes is shown in Figure 2.

Prebiotics and postbiotic/metabiotic approaches are mechanistically attractive because they may enhance SCFA production or deliver defined microbial metabolites without the variability of live-organism colonization [8]. Experimental work suggests that compounds such as butyrate can influence histone acetylation and mitochondrial signaling in preclinical systems [17, 66]. Yet human evidence remains sparse, and dose-response relationships, safety with chronic use, and the durability of benefits are not well characterized. For now, prebiotics and postbiotics should be considered emerging supportive strategies rather than validated antidepressant treatments.

One of the most significant challenges in microbiome research is the inherent variability in microbial composition and metabolic output across individuals. Genetics, diet, age, sex, geographical location, and medication use are all known to significantly alter microbial diversity and functionality [4, 21]. In clinical cohorts, antidepressant exposure may also confound microbiome analyses, complicating the interpretation of gut-brain interactions in treated individuals [20, 21]. Furthermore, individual host-microbe interactions profoundly impact the production of microbial metabolites, such as SCFAs and bile acids, which play a major role in mitochondrial activity and neuroprotection. This high degree of inter-individual variability necessitates a shift towards precision psychiatry, where therapeutic interventions are personalized based on an individual’s genetic history, microbiota composition, and lifestyle. Future research must focus on identifying robust microbial signatures that transcend individual differences or developing stratification strategies for patient cohorts.

The discovery of valid microbiome-mitochondrial biomarkers is a breakthrough point for clinical utility. Current MDD diagnostic systems predominantly rely on subjective symptomatology rather than objective molecular markers [4]. Developing composite biomarkers that incorporate microbial metabolites (e.g., SCFAs, tryptophan derivatives), mitochondrial respiration patterns, and inflammatory cytokines would be invaluable for determining disease severity, predicting treatment response, and monitoring adherence [89]. However, reproducibility remains a significant issue in biomarker research. Heterogeneous sampling approaches, sequencing platforms, and analysis pipelines contribute to discrepancies across studies. To achieve clinical reliability and widespread adoption, the standardization of data acquisition, normalization, and interpretation protocols will be critical.

The inherent complexity of MDD pathophysiology necessitates the use of multi-omics integration, including genomics, transcriptomics, proteomics, metabolomics, and metagenomics, to more comprehensively uncover interactions between the gut microbiota and host bioenergetic biology [86, 87]. Single-layer analyses often fail to capture the network-level biomolecular changes in bioenergetic and proinflammatory pathways that become visible in integrated systems approaches [86, 87]. For example, joint analysis of metagenomic, metabolomic, and host transcriptomic data can help identify microbial taxa and metabolites that are associated with mitochondrial signaling, oxidative phosphorylation, and treatment response in MDD [86, 87]. Computational integration of these datasets may help generate testable networks linking microbial metabolites, mitochondrial signaling, and treatment response in depression research [86, 87]. Such integrative methods are important for biomarker discovery, patient stratification, and response prediction in depression research [86, 87].

The rapid growth of computational biology and machine-learning approaches may eventually support more individualized MDD stratification, particularly when integrated with microbiome and metabolomic datasets. At present, however, these applications remain largely prospective rather than clinically validated in microbiota-mitochondria research [86, 87].

Despite the immense research potential and possibilities of microbiota-mitochondria modulation in psychiatry, significant challenges remain regarding translation and ethics. The long-term safety profiles of probiotics, prebiotics, and FMT are not yet fully characterized, particularly with respect to prolonged use, donor screening, engraftment durability, and adverse-event monitoring in psychiatric populations [85]. Ethical principles must also guide both microbiome manipulation and emerging mtDNA-editing strategies [93]. Moreover, ensuring equitable access to personalized psychobiotic interventions is crucial to avoid exacerbating existing mental health disparities globally. Future studies must prioritize cross-cultural follow-ups, research in low-resource settings, and the seamless incorporation of microbiota-derived therapies into general healthcare systems. Addressing these translational and ethical dimensions is paramount for the responsible and impactful advancement of this promising field.