Microbiome-Guided Antidepressant Therapy: The Future of Personalized Psychiatry Volume 60- Issue 4

Amália Cinthia Meneses do Rêgo¹ and Irami Araújo-Filho^1,2*

• ¹Institute of Teaching, Research, and Innovation, Liga Contra o Câncer, Full Professor of the Postgraduate Program in Biotechnology at Potiguar University, Potiguar University, (UnP), Brazil
• ²Institute of Teaching, Research, and Innovation, Liga Contra o Câncer, Full Professor of the Postgraduate Program in Biotechnology at Potiguar University (UnP) – Natal/RN – Brazil, Full Professor, Department of Surgery, Potiguar University, Ph.D. in Health Science, Brazil

Received: February 08, 2025; Published: February 20, 2025

*Corresponding author: Irami Araújo-Filho, Postgraduate Program in Biotechnology at Potiguar University/ UnP. Full Professor Department of Surgery, Federal University of Rio Grande do Norte, Full Professor, Department of Surgery, Potiguar University, Ph.D. in Health Science/ Natal-RN, Brazil, Av. Hermes da Fonseca, 1444 - Apto. 1302 - Tirol - Natal - State of Rio Grande do Norte – Brazil

DOI: 10.26717/BJSTR.2025.60.009477

Abstract PDF

Depression is a highly prevalent and heterogeneous disorder, often characterized by variable responses to antidepressant treatment. Recent research highlights the gut-brain axis as a critical modulator of psychiatric conditions, emphasizing the influence of microbiota on neurotransmitter synthesis, immune regulation, and systemic inflammation. Evidence suggests that gut dysbiosis contributes to treatment resistance, while specific bacterial strains, such as Lactobacillus and Bifidobacterium, enhance antidepressant efficacy. Conversely, pathogenic species promote neuroinflammation, impairing drug response. The emerging concept of microbiome-guided antidepressant therapy offers a precision medicine approach to optimizing psychiatric treatment. Advances in metagenomics, metabolomics, and artificial intelligence enable individualized treatment strategies, incorporating probiotics, prebiotics, and Fecal Microbiota Transplantation (FMT) as adjuncts to conventional pharmacotherapy. Studies suggest that microbiome modulation may enhance serotonin availability, reduce systemic inflammation, and improve antidepressant outcomes, particularly in treatment-resistant depression. Despite promising findings, several gaps remain regarding the long-term effects, optimal microbial interventions, and personalized therapeutic protocols. Additionally, age, sex, diet, and circadian rhythms influence microbiota composition, necessitating tailored interventions.

Future research should focus on identifying microbiota-based biomarkers to predict antidepressant response and integrate microbiome-based strategies into psychiatric practice. By harnessing the gut-brain axis, psychiatry is transitioning toward biologically informed, personalized mental health care, potentially revolutionizing the management of major depressive disorder. Microbiome-targeted therapies may bridge critical gaps in psychiatric treatment, improving clinical outcomes and paving the way for next-generation antidepressant strategies.

Keywords: Microbiota; Depressive Disorder; Major; Antidepressive Agents; Gut-Brain Axis; Precision Medicine; Probiotics

Abbreviations: FMT: Fecal Microbiota Transplantation; SSRIs: Selective Serotonin Reuptake Inhibitors; TCAs: Tricyclic Antidepressants; SNRIs: Serotonin-Norepinephrine Reuptake Inhibitors; MDD: Major Depressive Disorder; SCFAs: Short-Chain Fatty Acids; RCTs: Randomized Controlled Trials; TRD: Treatment-Resistant Depression; PTSD: Post-Traumatic Stress Disorder; CNS: Central Nervous System; MGBA: Microbiota-Gut-Brain Axis; LPS: Lipopolysaccharides; SCFAs: Short-Chain Fatty Acids; HPA: Hypothalamic-Pituitary-Adrenal; GAD: Generalized Anxiety Disorder; BD: Bipolar Disorder; PTSD: Post-Traumatic Stress Disorder

Depression remains one of the most prevalent and debilitating psychiatric disorders, affecting millions globally and contributing to substantial societal and economic burdens. Although antidepressant medications, including Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), and Tricyclic Antidepressants (TCAs), have been the cornerstone of pharmacological treatment, response rates remain highly variable (Figure 1) [1-3]. Up to one-third of patients with Major Depressive Disorder (MDD) exhibit inadequate response or develop treatment resistance. These necessitating prolonged trial-and-error approaches delay symptom relief and increase the risk of chronicity. These therapeutic inconsistencies underscore an urgent need for personalized treatment strategies that optimize efficacy and minimize adverse effects. Emerging research highlights the gut microbiome as a key determinant of antidepressant response, shaping the paradigm of microbiome-guided psychiatry [2-4]. The gut-brain axis is a complex bidirectional communication system integrating microbial, neural, endocrine, and immune pathways. This intricate network regulates neurotransmitter synthesis, neuroinflammation, and stress responses, all of which are implicated in depression pathophysiology. Dysbiosis, characterized by gut microbial imbalance, has been consistently observed in individuals with depression, with shifts in bacterial diversity and function linked to increased inflammatory markers and disrupted neurochemical homeostasis [3-5].

Figure 1

Variations in gut microbiota composition have been associated with depressive symptom severity, indicating that specific microbial signatures may be predictive biomarkers for treatment stratification. The mechanisms by which microbiota influences antidepressant efficacy are not yet understood [4-6]. Antidepressants themselves exert a profound impact on the gut microbiota. SSRIs, TCAs, and other psychotropic medications have been shown to modify the abundance of key bacterial taxa, leading to significant alterations in microbial metabolism [5-7]. Conversely, gut bacteria can bioaccumulate and metabolize antidepressants, influencing drug bioavailability, pharmacokinetics, and therapeutic response. This bidirectional interaction suggests that individual variations in microbiota composition may contribute to the heterogeneity observed in antidepressant efficacy and tolerability [6-8]. Some bacterial species can degrade or sequester pharmacological compounds, potentially reducing drug effectiveness or altering metabolic pathways involved in mood regulation. Despite these findings, the extent to which microbiome-antidepressant interactions shape clinical outcomes remains an open question, requiring further investigation [7-9]. Beyond direct drug-microbiome interactions, gut-derived metabolites exert significant neuromodulatory effects.

Short-Chain Fatty Acids (SCFAs), produced via bacterial fermentation of dietary fibers, play a crucial role in regulating neurogenesis, synaptic plasticity, and immune signalling—processes that are disrupted in MDD [8-10]. The microbial metabolism of tryptophan directly influences serotonin synthesis, impacting mood regulation and antidepressant effectiveness. Variations in microbial production of neurotransmitter precursors have been linked to differential antidepressant response, suggesting that microbial metabolic profiling could aid in predicting treatment outcomes [11]. Identifying gut-derived metabolites associated with therapeutic response represents a promising avenue for precision psychiatry. Yet, current research is still in its infancy, with inconsistencies across studies and limited longitudinal data [12]. A rapidly expanding area of interest involves the therapeutic modulation of gut microbiota through probiotic and prebiotic interventions. Several bacterial strains, including Lactobacillus and Bifidobacterium, have demonstrated antidepressant-like properties by reducing inflammation, enhancing serotonin availability, and modulating stress-related pathways [13-15]. Preliminary clinical evidence suggests that probiotic supplementation may improve antidepressant efficacy, particularly in individuals with gut dysbiosis or inflammatory phenotypes. However, critical knowledge gaps persist regarding optimal strain selection, dosage regimens, and long-term effects [16].

The heterogeneity of study designs and lack of standardized methodologies hinder the generalization of findings to clinical practice. Future investigations should focus on well-controlled trials incorporating microbiome profiling to validate these interventions [17]. Another pressing question concerns the role of gut microbiota in antidepressant resistance. Evidence indicates that specific microbial communities may confer resistance to pharmacological treatments by altering drug metabolism or modulating neuroimmune crosstalk. Chronic stress and inflammation—both key contributors to treatment-resistant depression—are closely linked to gut microbiota alterations [18,19]. Understanding the mechanisms by which microbial dysbiosis contributes to antidepressant non-response may pave the way for novel therapeutic strategies targeting the microbiome. Current clinical guidelines do not integrate microbiome analysis into the prescribing practices for antidepressants, indicating a significant translational gap within this area of study [20,21]. The implications of microbiome-mediated antidepressant response extend beyond adult populations. Emerging research suggests that prenatal and early-life microbiota exposures shape long-term neurodevelopmental trajectories, potentially influencing susceptibility to mood disorders later in life [22].

Antidepressant use during pregnancy and lactation has been shown to modulate maternal and neonatal gut microbiota, raising concerns about potential long-term neuropsychiatric consequences. These findings emphasize the need for further research exploring the intergenerational effects of microbiome alterations induced by psychotropic medications [23]. Despite the rapid advancements in microbiome research, several challenges remain. The complexity of microbiota-host interactions, interindividual variability, and confounding environmental factors such as diet and lifestyle complicate efforts to establish standardized microbiome-based predictive models [24]. Additionally, most available studies rely on cross-sectional designs, limiting causal inferences regarding microbiome-antidepressant interactions. Future research should prioritize longitudinal studies, functional metagenomics, and randomized controlled trials integrating microbiome profiling into antidepressant treatment protocols [25].

While the relationship between the gut microbiome and antidepressant response has gained considerable attention, fundamental gaps persist in understanding the mechanisms underlying microbiota- mediated treatment effects. The key unresolved questions include: What specific bacterial taxa or microbial metabolites predict antidepressant response or resistance? How do individual variations in microbiota composition influence drug metabolism, efficacy, and side effect profiles? Can targeted microbiome interventions, such as probiotics or dietary modifications, enhance antidepressant effectiveness in treatment-resistant populations?

What are the long-term effects of antidepressant-induced microbiota alterations, particularly in vulnerable populations such as pregnant individuals and neonates? How can microbiome profiling be integrated into clinical decision-making to optimize antidepressant therapy? [26-28]. This review aims to synthesize current evidence on microbiome-antidepressant interactions and explore the potential for microbiome-guided precision psychiatry. By critically evaluating microbial biomarkers for treatment response, mechanisms of drug metabolism, the impact of probiotic interventions, and emerging clinical applications, this work seeks to bridge the gap between microbiome research and psychiatric therapeutics. Understanding these complex interactions will be essential for advancing personalized approaches to depression treatment and optimizing therapeutic outcomes in the future (Figure 2) [29,30].

Figure 2

This review systematically examined the influence of the gut microbiota on managing and treating Major Depressive Disorder (MDD), focusing on the role of antidepressive agents, the gut-brain axis, precision medicine, and the potential therapeutic applications of probiotics. A comprehensive literature search was conducted across major scientific databases, including PubMed, Embase, Scopus, Web of Science, and Sicelo, supplemented by additional sources from gray literature searches on Google Scholar. The review included studies published to date to ensure a thorough evaluation of the most current and relevant evidence available. The search strategy was designed using a combination of keywords and MeSH terms tailored to the primary themes of this review. The selected terms included “Microbiota,” “Depressive Disorder, Major,” “Antidepressive Agents,” “Gut-Brain Axis,” “Precision Medicine,” and “Probiotics.” Boolean operators (AND, OR) were applied to construct precise and comprehensive search strings, ensuring the inclusion of a broad spectrum of relevant studies while maintaining specificity. Eligibility criteria were established to include various study designs, such as Randomized Controlled Trials (RCTs), cohort studies, case-control studies, cross-sectional studies, systematic reviews, and meta-analyses. Studies were selected based on whether they provided empirical data on microbiota-based interventions in depression, examined the interaction between gut microbiota and antidepressant efficacy, investigated the role of precision medicine in psychiatric treatment, or assessed the therapeutic impact of probiotics on mental health.

Exclusion criteria encompassed studies that lacked methodological rigor, did not directly explore microbiota’s role in depression, or presented only theoretical perspectives without empirical validation. Two reviewers conducted the selection process independently. They screened the titles and abstracts of the retrieved studies to identify potentially relevant articles. Any discrepancies were resolved through discussion, with a third reviewer consulted when necessary to achieve consensus. To minimize selection bias, the reviewers were blinded to the authorship and institutional affiliations of the included studies. Full-text articles that met the inclusion criteria were retrieved and systematically analyzed for relevance to the review’s objectives. Data extraction was performed using a standardized protocol to ensure consistency and reproducibility. Extracted data included study design, sample size, characteristics of the experimental model, gut microbiota composition, antidepressant treatments assessed, biomarkers evaluated, and patient outcomes related to microbiota-targeted interventions. The findings were categorized into key thematic areas, including the gut-brain axis modulation in MDD, probiotics’ role in improving depressive symptoms, microbiota-based precision psychiatry approaches, and gut microbial biomarkers predictive of antidepressant response. A critical evaluation of methodological quality was performed, highlighting potential biases, variations in study design, and inconsistencies in microbiota-targeted interventions across different clinical and experimental settings.

Particular attention was given to research gaps, including the lack of standardized protocols for microbiota-based treatment in depression, limited validation of gut microbiota biomarkers, and insufficient comparative studies assessing microbiome modulation versus conventional antidepressant therapies. Additional considerations included variability in microbiota profiling techniques, dataset heterogeneity, and potential biases in interpreting gut-brain interactions. This review also outlined future research directions, emphasizing the need for robust validation frameworks for microbiota-targeted psychiatric interventions, ethical considerations in gut microbiome research, the standardization of microbiota-based therapeutic protocols, and interdisciplinary collaborations among psychiatrists, microbiologists, and computational scientists. By synthesizing the current state of knowledge, this review underscores the transformative potential of microbiota-based approaches in enhancing antidepressant efficacy, advancing precision medicine in psychiatry, and shaping future strategies for personalized treatment of major depressive disorder.

The intricate relationship between gut microbiota and psychiatric disorders has emerged as a crucial factor in understanding depression, antidepressant response, and treatment resistance. Increasing evidence suggests that the gut microbiome influences neurotransmitter synthesis, immune modulation, and systemic inflammation, all of which play fundamental roles in the pathophysiology of Major Depressive Disorder (MDD) (Table 1) [31,32]. The concept of microbiome- guided antidepressant therapy represents a paradigm shift in psychiatry, moving toward precision medicine approaches that consider the unique microbial composition of each patient to optimize treatment efficacy. By leveraging the advances in microbiome science, clinicians may soon be able to personalize antidepressant therapy based on gut microbial biomarkers, dietary interventions, and microbiota- modulating therapeutics [33,34]. One of the most pressing challenges in treating MDD is the heterogeneity of antidepressant response. A significant proportion of patients do not achieve remission with conventional pharmacotherapy, and treatment resistance remains a substantial obstacle in clinical psychiatry [20]. Recent studies indicate that individual variations in gut microbiota composition may partially explain why some patients respond well to Selective Serotonin Reuptake Inhibitors (SSRIs) while others experience limited benefits or severe side effects [35].

Table 1: Microbiome-Guided Antidepressant Therapy.

Certain bacterial species, such as Bifidobacterium and Lactobacillus, have been linked to enhanced serotonin production. In contrast, an overabundance of pro-inflammatory microbes, such as Proteobacteria and Desulfovibrio, has been associated with increased neuroinflammation and reduced antidepressant efficacy. These findings suggest that modifying gut microbiota could enhance antidepressant response and potentially reduce the burden of Treatment-Resistant Depression (TRD) [36,37]. Beyond influencing antidepressant efficacy, gut microbiota has been implicated in the bidirectional relationship between depression and other psychiatric comorbidities, including anxiety, bipolar disorder, schizophrenia, and Post-Traumatic Stress Disorder (PTSD) [38]. Shared microbial dysfunctions across these conditions suggest that targeting gut microbiota may have broad-spectrum therapeutic effects across multiple psychiatric disorders. Additionally, studies have demonstrated that chronic stress and sleep disturbances contribute to gut dysbiosis, exacerbating depressive symptoms and increasing vulnerability to psychiatric conditions [39,40]. Circadian misalignment and sleep deprivation disrupts the gut microbiota’s rhythm, leading to reduced microbial diversity, increased intestinal permeability (“leaky gut”), and heightened neuroinflammatory responses. Understanding how sleep patterns and microbiome interactions influence depression could open new avenues for integrative treatment strategies that incorporate chronotherapy, light exposure, and microbiome-targeted interventions [41,42].

Emerging microbiome-based therapies offer promising alternatives or adjuncts to traditional antidepressants. Probiotics and prebiotics have shown potential in modulating gut microbiota and alleviating depressive symptoms, though their effects remain inconsistent due to strain-specific variability and individual differences in microbiome composition [43,44]. More advanced interventions, such as engineered probiotics and bacteriophage therapy, are currently being explored as highly targeted approaches to restore microbial balance. Additionally, Fecal Microbiota Transplantation (FMT) is being investigated as a potential treatment for severe, treatment-resistant depression, with early findings suggesting that transferring microbiota from healthy donors may positively influence mood and cognitive function. However, the long-term safety and feasibility of FMT in psychiatric disorders remain determined [45,46]. Another critical area of research is the role of nutritional psychiatry and microbiota-driven dietary interventions. Diet is a significant modulator of gut microbiota composition, and specific nutritional patterns—such as the Mediterranean diet—have been associated with increased microbial diversity, reduced systemic inflammation, and improved mood regulation [47]. In contrast, Western diets high in processed foods, refined sugars, and artificial additives are correlated with gut dysbiosis and a heightened risk of depression [22].

Based on an individual’s microbiota profile, personalized dietary interventions could enhance antidepressant response and overall mental well-being. Future research should explore whether microbiome- based nutritional strategies can be tailored to optimize psychiatric treatment outcomes [30-32]. Sex differences in microbiota composition and antidepressant response represent another critical factor in personalized psychiatry. Men and women exhibit distinct gut microbial profiles influenced by hormonal fluctuations, immune system regulation, and genetic predisposition. Estrogen has been shown to promote the growth of anti-inflammatory bacterial species, which may explain why women, despite having a higher prevalence of depression, often respond more favourably to SSRIs than men [47-49]. Conversely, testosterone is associated with greater microbial diversity and enhanced stress resilience, potentially influencing sex-specific vulnerabilities to depression. Future research should investigate gender-specific microbiota interventions, including sex-adapted probiotics and dietary modifications, to further refine antidepressant therapy [16-18]. As the field progresses, integrating microbiome research into psychiatric practice holds tremendous potential for revolutionizing mental health treatment. Future clinical trials should focus on identifying microbiome-based biomarkers for antidepressant response, optimizing microbiota-targeted therapies, and developing individualized treatment protocols [7-10].

Advances in machine learning and artificial intelligence could further aid in predicting treatment outcomes based on gut microbiota signatures, paving the way for a more precise, effective, and personalized approach to depression management [38,45]. Ultimately, the concept of microbiome-guided antidepressant therapy represents a transformative shift in psychiatry, redefining how depression is understood and treated. By bridging the gap between neuroscience, microbiology, and clinical psychiatry, researchers and clinicians can develop novel interventions that harness the power of the gut-brain axis to optimize mental health outcomes [49-51]. The future of depression treatment lies in pharmacological innovation and the personalized modulation of gut microbiota to enhance therapeutic efficacy and long-term patient well-being [24].

The Microbiota-Gut-Brain Axis as a Central Regulator of Antidepressant Response

The Microbiota-Gut-Brain Axis (MGBA) is a highly complex communication network that links the gastrointestinal microbiota with the Central Nervous System (CNS) through neural, endocrine, and immune pathways [36]. Over the past two decades, growing evidence has demonstrated that gut microbiota is essential in modulating neurotransmission, regulating inflammation, and influencing antidepressant metabolism [10]. Patients with Major Depressive Disorder (MDD) exhibit significant gut dysbiosis, characterized by reduced microbial diversity, an overrepresentation of pro-inflammatory taxa, and decreased levels of beneficial species such as Bifidobacterium and Lactobacillus [27]. These microbial imbalances are associated with elevated systemic inflammation, neuroinflammation, and altered tryptophan metabolism, all of which have been implicated in the pathophysiology of depression [42]. Despite these associations, it remains unclear whether gut dysbiosis is a cause or consequence of MDD. Several longitudinal studies have suggested that gut microbial shifts may precede the onset of depressive symptoms, implying a causal role in disease development [6,7]. Antidepressant treatment itself has been shown to alter gut microbiota composition, making it difficult to determine whether microbiome changes are a driver or an effect of antidepressant therapy. For example, SSRIs such as fluoxetine have increased microbial diversity in some individuals but exacerbated dysbiosis in others, highlighting significant interindividual variability in microbiota-drug interactions [19-21].

One of the most critical aspects of MGBA dysfunction in MDD is intestinal permeability and systemic inflammation. Many depressed individuals exhibit increased gut permeability, often called “leaky gut,” which facilitates the translocation of bacterial endotoxins such as Lipopolysaccharides (LPS) into circulation [40,41]. This triggers immune activation and systemic inflammation, further exacerbating neuroinflammation and contributing to reduced serotoninergic neurotransmission and impaired synaptic plasticity. Given that inflammation is a major contributor to antidepressant resistance, targeting gut microbiota to restore gut barrier integrity and reduce inflammatory burden represents a promising avenue for intervention [25-28]. The MGBA also regulates the production of Short-Chain Fatty Acids (SCFAs), including butyrate, propionate, and acetate, which exert neuroprotective effects by promoting neurogenesis, modulating synaptic plasticity, and enhancing anti-inflammatory pathways [3-5]. Dysregulated tryptophan metabolism in MDD patients has been linked to increased kynurenine pathway activation, resulting in neurotoxic metabolite production that impairs neuroplasticity and contributes to depressive symptomatology. Understanding how microbial-derived metabolites influence antidepressant efficacy may pave the way for novel therapeutic approaches that enhance antidepressant response through microbiome modulation [39-42].

Genetic and Molecular Interactions Between Gut Microbiota and Antidepressants

The gut microbiome influences the antidepressant response through microbial composition and genetic and molecular mechanisms. Genetic polymorphisms in serotonin transport and immune regulation genes have been identified as potential determinants of antidepressant efficacy, and recent findings suggest that gut microbiota may modulate these genetic pathways [17-19]. The SLC6A4 gene, which encodes the serotonin transporter (5-HTT), has been widely studied concerning antidepressant response variability, and emerging evidence suggests that gut microbiota can modulate serotoninergic tone by influencing tryptophan metabolism and serotonin bioavailability [6,44]. Gut bacteria also play an active role in drug metabolism, affecting antidepressant pharmacokinetics and bioavailability. Certain bacterial species, including Bacteroides and Firmicutes, harbor enzymes that modify the chemical structure of antidepressants, altering their therapeutic potential [14-16]. Moreover, gut microbiota influences hepatic cytochrome P450 enzyme activity, indirectly modulating the metabolism of antidepressants such as SSRIs, SNRIs, and TCAs. This suggests that gut microbiome composition may serve as a predictive biomarker for individual drug response, helping to personalize pharmacotherapy in psychiatry [28,50]. Beyond serotonin metabolism, gut microbiota regulates dopaminergic and GABAergic signalling, two critical pathways in mood regulation and antidepressant mechanisms.

Certain strains of Lactobacillus and Bifidobacterium have been shown to enhance GABA production, exerting anxiolytic effects, while others modulate dopamine biosynthesis, potentially influencing motivation, anhedonia, and reward processing in depression [35,46]. Understanding how microbiota-derived neurotransmitters interact with antidepressant mechanisms may lead to developing next-generation microbiome-based therapies that enhance antidepressant efficacy [13].

The Role of Microbiota in Antidepressant Resistance and Personalized Therapy

Antidepressant resistance remains a major clinical challenge, affecting up to 30% of MDD patients. Increasing evidence suggests that gut microbiota composition is crucial in modulating treatment response, with specific microbial signatures linked to treatment-resistant depression (TRD). Patients with TRD frequently exhibit higher levels of inflammatory microbiota, which may counteract the anti-inflammatory and neuroprotective effects of antidepressants [48-51].

One promising approach to overcoming antidepressant resistance is using microbiome-targeted interventions, including probiotics, prebiotics, and dietary modifications. While early studies have shown that probiotics can modulate inflammatory pathways and enhance serotoninergic neurotransmission, their efficacy in augmenting antidepressant response remains inconsistent, likely due to strain-specific effects and interindividual variability [2,15,34]. A more advanced strategy involves Fecal Microbiota Transplantation (FMT), which has been explored as a potential intervention for restoring gut microbial balance in TRD. Preclinical models have demonstrated that transplanting gut microbiota from healthy individuals into depressed animals can alleviate depressive symptoms, suggesting that FMT may hold therapeutic promise in MDD. However, clinical studies evaluating FMT in psychiatry remain limited, and further research is required to establish long-term safety and efficacy [18,32,49].

Future research should focus on identifying microbial biomarkers of antidepressant response and developing precision psychiatry models that integrate microbiome diagnostics into clinical practice. By personalizing antidepressant therapy based on microbiota composition, clinicians may improve treatment outcomes and reduce the trial-and-error approach currently used in psychiatry [50,51].

The Role of the Microbiome in the Comorbidity Between Depression and Other Psychiatric Disorders

Depression is often presented alongside other psychiatric disorders, including Generalized Anxiety Disorder (GAD), Bipolar Disorder (BD), schizophrenia, and Post-Traumatic Stress Disorder (PTSD). This frequent overlap suggests the existence of shared neurobiological and microbiome-driven mechanisms contributing to psychiatric comorbidities [3,12,40]. The gut microbiota plays a central role in modulating inflammation, neurotransmitter production, and the Hypothalamic-Pituitary-Adrenal (HPA) axis, all dysregulated in these conditions. Understanding whether these disorders stem from a common microbiome dysfunction is crucial in neuropsychiatry [17,23]. Evidence from multiple studies has shown that patients with GAD exhibit gut microbial alterations like those seen in MDD, including an increased abundance of pro-inflammatory bacteria (Proteobacteria, Desulfovibrio) and reduced levels of beneficial strains such as Bifidobacterium and Lactobacillus. The gut microbiota influences the HPA axis, which regulates cortisol secretion and stress responses [33,49]. Given that HPA axis dysregulation is a hallmark of both anxiety and depression, it is plausible that gut microbiota influences both conditions through altered neuroendocrine signalling. Several clinical trials have explored the use of probiotics and prebiotics to modulate stress responses and anxiety symptoms, but their efficacy remains inconsistent due to interindividual variability in microbiome composition [16,38].

Bipolar disorder presents another compelling case of microbiota involvement in mood instability and treatment resistance. Patients with BD exhibit lower levels of Faecalibacterium prausnitzii, an anti-inflammatory bacterium essential for gut homeostasis, and an overrepresentation of bacterial species associated with oxidative stress and neuroinflammation [24,51]. Interestingly, mood stabilizers such as lithium and valproate have been shown to alter gut microbiota composition, although whether these changes contribute to therapeutic benefits or side effects remain unclear. Some researchers suggest that gut-targeted interventions, including dietary modifications and microbiota transplants, could be explored as adjunctive treatments to stabilize mood fluctuations [9,17,46]. Schizophrenia provides an additional dimension to the microbiota-psychiatric disorder connection. Studies have shown that patients with schizophrenia display significant gut microbiota alterations, including increased Lactobacillus levels and reduced Bacteroides. One of the most intriguing hypotheses is that gut microbiota influences glutamatergic neurotransmission, a key mechanism implicated in psychosis [1-3,18].

If microbiota-targeted interventions could modulate glutamate and dopamine balance, they might offer a novel therapeutic approach to managing schizophrenia symptoms. Future research should focus on whether FMT or next-generation probiotics could be used to correct microbiota-driven neurotransmitter imbalances in schizophrenia [20-22].

Given these findings, the concept of a shared gut-microbiome- based pathophysiology among psychiatric disorders is emerging as a novel framework in neuropsychiatry [15]. Research should focus on identifying common microbial signatures across psychiatric conditions and determining whether microbiota-targeted interventions can serve as broad-spectrum psychiatric treatments [31]. Integrating microbiome diagnostics in psychiatry may eventually allow clinicians to stratify patients based on their gut microbial profiles and provide more tailored, individualized therapies [50].

Influence of Sleep and Circadian Rhythm on the Microbiome and Depression

The interplay between circadian rhythms, sleep quality, and the gut microbiome is an emerging field in depression research. Circadian rhythms regulate hormonal fluctuations, metabolic cycles, and immune function, directly and indirectly affecting gut microbiota composition [44-47]. In turn, the gut microbiota follows a diurnal cycle, with specific bacterial species fluctuating in abundance based on host sleep-wake patterns. Disruptions in circadian homeostasis— such as those caused by chronic insomnia, shift work, or irregular sleep schedules—can induce microbiome alterations that exacerbate depressive symptoms [36-38]. Studies have shown that individuals with sleep disorders, including insomnia and hypersomnia, often exhibit gut dysbiosis characterized by reduced microbial diversity and an overrepresentation of pro-inflammatory taxa. Melatonin, a key regulator of circadian rhythms, has been shown to modulate gut microbiota composition [4-6]. Interestingly, melatonin supplementation in animal models has been found to restore microbial diversity and reduce neuroinflammation, suggesting that melatonin-based interventions could be explored as microbiome modulators in depression [10]. Another critical finding is that sleep deprivation directly affects gut microbiota composition. Experimental studies have demonstrated that chronic sleep restriction leads to an overgrowth of pro-inflammatory bacterial species and a depletion of beneficial microbes such as Akkermansia muciniphila.

Since gut permeability (“leaky gut”) has been linked to MDD, sleep disturbances may aggravate gut barrier dysfunction, further increasing systemic inflammation and neuroinflammatory responses [8,14]. Chronotherapeutic approaches, such as light therapy, structured sleep-wake cycle interventions, and timed probiotic administration, are being investigated for their potential to realign circadian rhythms and restore microbial balance. If these interventions prove effective, they could be integrated into personalized treatment strategies for depression, targeting both sleep disturbances and microbiome imbalances simultaneously [30,34]. Given these insights, future research should explore how sleep quality influences gut microbiota dynamics and whether correcting circadian misalignment can enhance antidepressant response. The bidirectional relationship between the microbiome and sleep architecture represents an exciting frontier in psychiatry that could lead to novel microbiome-based sleep therapeutics [48,49].

Future Therapeutic Strategies: Microbiome Engineering and Genetic Modifications

The emerging field of microbiome engineering and genetic modification offers groundbreaking possibilities for psychiatric treatment. Traditional probiotics have shown inconsistent results in treating depression, likely due to interindividual variability in microbiota composition and the inability of conventional probiotics to colonize the gut long-term [5,17]. Researchers are developing engineered bacterial strains to address these limitations, enhancing neurotransmitter biosynthesis, regulating immune function, and improving gut barrier integrity. These next-generation probiotics could provide more targeted and reliable benefits than traditional formulations [18,29]. One of the most promising advances in microbiome engineering involves the modification of Lactobacillus and Bifidobacterium strains to produce serotonin and dopamine precursors, potentially enhancing the bioavailability of these key neurotransmitters [30]. Experimental models have demonstrated that gut-derived serotonin production influences mood regulation, suggesting that engineered probiotics could serve as adjuncts to traditional antidepressant therapy. If clinically validated, these innovations may pave the way for microbiota-based treatments tailored to specific neurotransmitter imbalances in depression [34,35,48]. Another cutting-edge approach is bacteriophage therapy, which selects viruses to target and selectively eliminate specific bacterial species.

Given that gut dysbiosis in depression is often characterized by an overgrowth of pro-inflammatory bacteria, bacteriophage therapy could provide an exact method to restore microbial balance without disrupting beneficial microbiota. Unlike broad-spectrum antibiotics, which kill both pathogenic and beneficial bacteria, bacteriophage therapy is highly selective, minimizing the risk of microbiota depletion [27,33,37]. CRISPR-based microbiota editing is another revolutionary concept. By leveraging CRISPR-Cas9 gene-editing technology, researchers are exploring selectively modifying bacterial genomes to enhance their therapeutic potential. This could allow the engineering of microbial strains capable of modulating inflammation, reducing gut permeability, and synthesizing neuroactive compounds. Although this technology is still in its infancy, it represents a paradigm shift in microbiome-based medicine, with the potential to create customized microbial therapies for psychiatric disorders [14,26,42]. Future clinical trials will determine whether these advanced microbiome therapies can be integrated into psychiatric practice. If successful, engineered microbiota-based treatments could offer a new frontier in precision psychiatry. They would move away from the one-size-fits-all approach toward customized, microbiome-driven interventions tailored to each patient’s unique gut microbial profile [9-13].

Nutritional Psychiatry: The Role of Diet in Modulating the Microbiota and Antidepressant Response

Diet plays a critical role in shaping the gut microbiota, and growing evidence suggests that nutritional interventions may influence antidepressant efficacy. The link between diet, microbiota composition, and mental health is at the core of nutritional psychiatry, a rapidly expanding field investigating how specific dietary patterns and nutrients modulate mood disorders. Emerging data suggest microbiota- targeted dietary strategies could be an adjunctive approach to antidepressant therapy, optimizing treatment outcomes [27,38,44]. Several key dietary components have been identified as modulators of gut microbiota and mental health, including [6,20,32]:

• Polyphenols (found in berries, green tea, and dark chocolate) – Promote the growth of beneficial bacteria and reduce oxidative stress.

• Prebiotic fibers (found in garlic, onions, bananas) – Enhance Bifidobacterium and Lactobacillus, improving gut integrity and reducing inflammation.

• Omega-3 fatty acids (found in fatty fish and flaxseeds) – Exhibit anti-inflammatory properties and improve neurogenesis.

• Fermented foods (such as yogurt, kimchi, and kefir) – Provide live bacterial strains that can restore microbial diversity and influence serotonergic pathways.

One of the most well-studied dietary interventions is the Mediterranean diet, which is rich in fiber, healthy fats, and polyphenols. Studies have shown that adherence to a Mediterranean-style diet is associated with increased microbial diversity and reduced levels of systemic inflammation, which correlate with lower rates of depression and improved antidepressant response [8-10]. In contrast, Western diets, which are high in processed foods, refined sugars, and artificial additives, have been linked to gut dysbiosis and a higher prevalence of psychiatric disorders [19]. An up-and-coming area of research is personalized nutrition based on microbiome composition. Given the interindividual variability in gut microbiota, a personalized dietary approach tailored to a patient’s specific microbial profile could optimize antidepressant therapy. Microbiome-based nutritional interventions could enhance treatment response, reducing the trial-and-error approach currently employed in psychiatry [29,34,48]. Future research should investigate how microbiota-informed dietary strategies can be integrated into clinical practice. The potential for combining microbiome assessments with personalized nutrition plans could revolutionize the way psychiatric disorders are treated, offering a more holistic and individualized approach to mental health care [27-29].

Sex Differences in Microbiota Composition and Antidepressant Response

Sex differences in depression prevalence and treatment response are well-documented, and recent studies suggest that gut microbiota may play a role in these differences. Men and women exhibit distinct gut microbial compositions influenced by hormonal fluctuations, immune system function, and genetic predisposition. Understanding how sex-specific microbiota differences influence antidepressant response could lead to the development of gender-specific microbiota- targeted interventions, further optimizing psychiatric treatment [15,27,36]. One of the primary factors driving sex differences in microbiota composition is hormonal regulation. Estrogen has been shown to modulate gut microbiota, promoting the growth of anti-inflammatory bacterial species, while testosterone is associated with increased microbial diversity and enhanced stress resilience. This may partially explain why women have a higher prevalence of depression but tend to respond better to certain antidepressants compared to men [41-43]. Another key consideration is the differences in immune systems between the sexes. Women have a more robust immune response, which may influence how gut microbiota interact with inflammatory pathways involved in depression. Studies have shown that pro-inflammatory cytokines differentially affect male and female brains, potentially altering the efficacy of microbiota-targeted interventions [44,45].

The impact of gut microbiota on antidepressant metabolism also appears to vary between sexes. Certain bacterial strains influence hepatic enzyme activity, affecting how antidepressants are metabolized and eliminated from the body. If specific gut microbial signatures are identified as predictors of sex-specific treatment response, microbiota- targeted therapies could be personalized separately for male and female patients [14,46]. Despite these findings, the integration of sex-based microbiome research into clinical practice remains limited. Future research should prioritize longitudinal studies investigating microbiota-sex interactions and whether gender-specific probiotic or dietary interventions could optimize antidepressant efficacy. By addressing these knowledge gaps, precision psychiatry could move toward truly personalized, sex-informed microbiome therapies [47-51].

Microbiome-guided antidepressant therapy represents a transformative shift in psychiatry, offering a personalized and biologically informed approach to depression treatment. The gut microbiota plays a fundamental role in neurotransmitter regulation, immune modulation, and systemic inflammation, directly influencing antidepressant efficacy and treatment resistance. Emerging evidence suggests that modulating gut microbiota through probiotics, prebiotics, Fecal Microbiota Transplantation (FMT), and engineered bacterial strains may enhance therapeutic outcomes, particularly in patients With Treatment-Resistant Depression (TRD). However, further research is needed to establish standardized microbiota-based interventions, determine long-term effects, and optimize integration with existing psychiatric treatments.

Beyond its impact on antidepressant response, the microbiome is intricately linked to psychiatric comorbidities, circadian rhythms, and sex-specific differences in mental health outcomes, reinforcing the importance of precision psychiatry approaches. Future studies should focus on identifying microbiota-based biomarkers, optimizing individualized treatment strategies, and integrating microbiome diagnostics into routine psychiatric care. Harnessing the gut-brain axis opens new frontiers in psychiatry. It enables a transition from generalized pharmacotherapy to be targeted interventions that address individual variations in microbiota composition. By incorporating microbiome- based therapies, psychiatry can move toward more effective, personalized, and holistic treatment paradigms, ultimately improving patient outcomes and reshaping the future of mental health care.

The authors thank the Federal University of Rio Grande do Norte, Potiguar University, and Liga Contra o Cancer for supporting this study.

The authors declare that there is no conflict of interest.

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