Transforming mental health: The future of personalized psychobiotics in anxiety and depression therapy

Gilberto Uriel Rosas Sánchez^1,2*José Luis Muñoz-Carrillo^1,2Cesar Soria Fregozo^1,2

• ¹Universidad de Guadalajara, Guadalajara, Mexico
• ²Universidad de Guadalajara - Centro Universitario de Los Lagos, Lagos de Moreno, Mexico

The incidence and prevalence of anxiety and depression continue to rise, and conventional pharmacotherapies offer only incomplete solutions for millions of patients around the world. At the same time, scientific insights into the microbiota-gut-brain axis have opened up unprecedented opportunities for therapeutic innovation. Recent literature suggests a positive role for probiotics in the treatment of depression and anxiety (1); however, the heterogeneity of therapeutic responses suggests that current approaches do not account for individual differences in microbial ecology and hostmicrobe interactions (2). The concept of psychobiotics-probiotics with positive effects on mental health -has evolved from empirical observations to a mechanistic understanding (3,4). However, the field is at a critical juncture where generic interventions must give way to personalized approaches (5). The rapidly growing field of microbiome-directed therapeutics has attracted significant attention due to its potential to revolutionize healthcare (6) and represents a fundamental shift from population-based to precision medicine paradigms. This transition is particularly urgent as understanding how broad host-microbiome associations are maintained across populations reveals individualized hostmicrobiome phenotypes that can be integrated with other 'omics' datasets to improve precision medicine (7,8). This opinion piece will address the potential of probiotics and psychobiotics as precision medicine tools in the treatment of anxiety disorders and depression. The current state of scientific evidence, the neurobiological mechanisms involved, limitations of the field, and future prospects for the design of individualized interventions will be discussed, with an emphasis on the integration of 'omics' approaches and bioinformatics technologies. Mechanisms beyond traditional neurotransmission Research demonstrates substantial evidence for probiotic production and modulation of neurotransmitters through the gut-brain axis, the mechanistic basis for the efficacy of psychobiotics goes far beyond traditional psychiatric pharmacology (9). Gut bacteria can influence the production and regulation of neurotransmitters such as dopamine, acetylcholine, gamma-aminobutyric acid (GABA) and serotonin and affect their availability in the brain (9,10). Certain bacterial strains show a remarkable ability to directly synthesize neurotransmitters, with several species being among the documented producers of neuroactive compounds (11). Recent discoveries in neuromicrobiology have elucidated sophisticated signaling networks (12). GABA signaling networks in the brain-gutmicrobiome axis involve multiple pathways, including activation of GABA receptors in the gut nervous system, activation of the immune system, and GABA-stimulated exosome-mediated signaling (13). This multi-target approach distinguishes the psychobiotic mechanisms from conventional antidepressants, which generally modulate single neurotransmitter systems. The clinical relevance of these mechanisms is demonstrated by direct interventions showing that targeted microbial modulation can effectively influence central nervous system function via peripheral signaling pathways (14), providing tangible evidence for the therapeutic potential of precision microbiome interventions (Figure 1). In addition to the production of neurotransmitters, psychobiotics influence neuroinflammation through complex immunomodulatory mechanisms reducing the production of proinflammatory cytokines such as IL-1β, TNF-α and IL-6, while promoting anti-inflammatory mediators such as IL-10 (9,15). The gut-brain axis is a bidirectional communication network that connects the enteric and the central nervous system (CNS) and also includes endocrine, humoral, metabolic and immunological communication pathways (16). This comprehensive network enables the simultaneous influence of inflammation, neurotransmission and neuroendocrine function. Probiotics indirectly alter CNS function by producing metabolites that influence serotonin levels, brain-derived neurotrophic factor (BDNF), dopamine and GABA (17,18). The integration of these mechanisms leads to synergistic therapeutic effects that go beyond individual signaling pathways and create a comprehensive neurochemical network suitable for microbial interventions (Figure 1).Insert Figure 1 here The clinical evidence for the efficacy of psychobiotics has evolved considerably, with recent metaanalysis providing nuanced perspectives on therapeutic potential (19,20). A random-effects metaanalysis of 34 controlled clinical trials investigating the effects of prebiotics and probiotics on depression and anxiety found heterogeneous but promising results (21,22). In particular, taking probiotics for up to four, eight and twelve weeks is effective in reducing depressive and anxiety symptoms in clinically diagnosed patients compared to placebo (23,24). However, the evidence also has important limitations. It may be premature to conclude clinical efficacy in relieving anxiety, as the effect size is small and there is no consensus on the optimal dose, treatment duration or specific formulations (25). These findings highlight the need for a personalized approach that takes into account individual variability in response to treatment. Recent analyses indicate that specific strains-such as Lacticaseibacillus casei Shirota, Lactobacillus gasseri CP2305, Lactiplantibacillus plantarum PS128, Lacticaseibacillus rhamnosus LR06, and Bifidobacterium longum subsp. longum R0175 have shown efficacy in alleviating anxiety and depression symptoms (26)(27). This strain-level activity supports the development of precision psychobiotic interventions. The heterogeneity in treatment responses across studies reflects fundamental individual differences in microbiome composition, host genetics, and environmental factors (28). The current review suggests that probiotics may improve symptoms of depression and anxiety in clinical patients; however, given the limitations in the included studies, randomized controlled trials (RCTs) with long-term follow-up and large sample sizes are needed (29). This variability represents both a challenge and an opportunity for precision medicine approaches. Understanding the biological basis for differential responses will enable stratification of patients based on predictive biomarkers (30), optimizing therapeutic outcomes while minimizing unnecessary interventions. It is essential to recognize that, despite advances, the heterogeneity in clinical study results reflects the complexity of the microbiome and its interaction with genetic and environmental factors. The lack of standardized protocols, in addition to variability in individual microbial composition, limits the reproducibility and clinical applicability of probiotic interventions. These aspects should be considered in future research to optimize their clinical utility. The transition to precision psychobiotics requires a fundamental reconceptualization of therapeutic approaches based on individual biological profiles (31). The concept of the "precision microbiome" involves the precise analysis and typing of the microbiota in specific hosts using advanced tools such as high-throughput sequencing, genomics and artificial intelligence. This technological foundation enables comprehensive characterization of individual microbiome signatures that could predict treatment response. The inherent individuality of the composition of the microbiome requires personalized therapeutic strategies rather than one-size-fits-all solutions (32). The genomic revolution promises to transform our approach to treating patients by individualizing treatments, reducing side effects and lowering healthcare costs (33), with microbiome analysis being a critical component of this transformation. Advanced analytical approaches are revolutionizing the personalization of treatments by integrating multiple data streams (34). Precise reconstitution of the microbiome using high-throughput sequencing and artificial intelligence tools enables real-time monitoring and optimization of therapeutic interventions based on the dynamics of the individual microbiome (32,35). The application of these technologies facilitates unprecedented precision in the selection and monitoring of therapies. A new approach to treating disease through personalized probiotic therapies-also known as precision medicine-has been proposed by researchers (34,35), demonstrating the feasibility of individualized microbial interventions in various therapeutic areas. The integration of 'omics' technologies-such as genomics, metabolomics, and microbiomics-allows for the identification of specific microbial profiles associated with positive or adverse responses to probiotics. These strategies pave the way for personalized therapies, where the selection of specific strains and combinations is tailored to a patient's unique microbial signature. Recent studies have exemplified how the analysis of these signatures can predict treatment efficacy, reaffirming the importance of a personalized medicine approach. The future of precision psychobiotics requires a deeper mechanistic understanding of host-microbe interactions in mental health (31). Psychobiotics are probiotic strains capable of influencing the gutbrain axis and have been shown to be effective in several neurological disorders (11). To make progress in this field, a comprehensive mapping of microbial metabolic pathways, host genetic variants and environmental factors influencing therapeutic outcomes is required (36). In psychobiotics, the potential of probiotics to influence the nervous system and mental health is being investigated through a comprehensive analysis of their effects on mood, cognition and stress response (14). This mechanistic foundation will enable the rational design of personalized treatment regimens optimized for individual patients. The transition from research to clinical practice requires addressing multiple challenges while taking advantage of the opportunities that arise. Standardization of analytical protocols, validation of predictive biomarkers and integration into existing psychiatric care are crucial prerequisites for implementation (10,37). For example, in a recent pilot study, patients with major depressive disorder showed significant improvements after receiving a personalized probiotic regimen based on their baseline microbiome profile (38)(39)(40). These experiences, although preliminary, illustrate the feasibility and potential of personalized microbiome-centered therapies and underscore the need for larger-scale controlled trials. The development of precision psychobiotics requires interdisciplinary collaboration between microbiologists, psychiatrists, bioinformaticians and regulatory specialists. This collaborative approach will accelerate the translation of mechanistic insights into clinically applicable interventions to improve patient outcomes. The development of personalized microbiome therapies faces significant challenges, including regulatory hurdles, the costs of omics analysis, and ethical issues related to microbiome modification. Furthermore, it is essential to define reliable predictive biomarkers and establish clear clinical criteria for their use. Multidisciplinary collaboration, integrating microbiology, psychiatry, bioinformatics, and regulation, will be key to overcoming these barriers and bringing these innovations into routine clinical practice. The emergence of precision psychobiotics represents a convergence of multiple scientific advances that collectively challenge traditional approaches to mental health treatment. The evidence synthesized in this review reveals both unprecedented opportunities and significant challenges that must be addressed to realize the full therapeutic potential of personalized microbiome interventions. The mechanistic foundations for psychobiotic efficacy are increasingly well-established, with robust evidence for neurotransmitter production (3,13), neuroinflammatory modulation (16,18), and multipathway signaling networks (14). However, translating these mechanistic insights into clinically effective interventions remains complex. The heterogeneity observed in meta-analysis (21,22,25) suggests that individual differences in microbiome composition, host genetics, and environmental factors significantly influence treatment outcomes. This variability underscores the necessity for precision medicine approaches that can stratify patients based on predictive biomarkers (30,32). The challenge lies in identifying which combinations of microbial, genetic, and clinical factors best predict treatment response, requiring sophisticated analytical approaches that integrate multi-omics data (7,8).Several critical limitations constrain current progress toward precision psychobiotics. The complexity of microbiome-brain interactions creates analytical challenges that exceed current technological capabilities (8,41). Additionally, the temporal dynamics of microbial communities introduce variability that complicates therapeutic monitoring and optimization. RTCs have shown that probiotic treatment for 4 and 12 weeks does not pose a relative risk of treatment-associated adverse events, even in patients with irritable bowel syndrome (42,43). The preponderance of evidence, including the long history of safe use of probiotics, as well as data from clinical trials and animal and in vitro studies, supports the assumption that probiotics are generally safe for most populations (44). Future research should address heterogeneity in diagnosis and intervention types to better understand their efficacy (45). The field requires rigorous adherence to evidence-based standards while resisting pressure for rapid commercialization of insufficiently validated interventions. Long-term safety considerations remain largely unexplored, particularly regarding potential unintended consequences of targeted microbial manipulation (1). Comprehensive safety assessment protocols must accompany therapeutic development to ensure patient welfare throughout treatment courses.The transition to precision psychobiotics will require fundamental changes in clinical practice patterns, including integration of microbiome analysis into psychiatric assessment protocols (34,38). This transformation necessitates substantial investment in diagnostic infrastructure, clinician training, and regulatory frameworks that can accommodate personalized interventions while maintaining safety standards. The economic implications are equally significant, as precision medicine approaches typically involve higher upfront costs for diagnostic testing and personalized formulation development. However, the potential for improved treatment outcomes and reduced healthcare utilization costs may justify these investments over the long term. As we advance toward this future, the mental health community must embrace the complexity inherent in personalized medicine while maintaining focus on the ultimate goal: improving patient outcomes through scientifically rigorous, individually tailored therapeutic interventions. The transformation of probiotics from generic supplements to precision medicine tools represents both a scientific achievement and a moral imperative to provide the most effective possible care for patients suffering from anxiety and depression. This article proposes an innovative approach that combines recent scientific evidence, critical analysis, and a forward-looking perspective that emphasizes the convergence of microbiology, neuroscience, and personalized medicine. Its originality lies in contextualizing probiotic therapy within the precision medicine paradigm, offering both conceptual and practical insights, and proposing concrete pathways for its integration into clinical care.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.