Targeting probiotic modulation of gut microbiota for postoperative depression management in patients undergoing gastric cancer surgery

Abstract

Postoperative depression is a prevalent yet often overlooked complication following radical surgery for gastric cancer that significantly affects patient recovery and quality of life. Emerging evidence suggests that the gut microbiota has a crucial role in the gut-brain axis, influencing mood regulation and psychological resilience. In the study by Lu et al, Bifidobacterium triple viable bacteria combined with mirtazapine demonstrated marked efficacy: The observation group showed a 32% reduction in Self-Rating Depression Scale depression scores, significantly outperforming the control group. Neuroendocrine improvements included a 89% increase in dopamine and a 43% reduction in cortisol. Gut microbiota modulation was evident with Bifidobacterium colony counts rising by 22%, while Escherichia coli decreased by 28%. Quality of life scores improved by 39%, underscoring the therapy’s holistic benefits. These findings validate the synergistic potential of microbiota-targeted probiotics and psychotropic drugs. Early screening, multidisciplinary care, and personalized strategies integrating psychological support, dietary optimization, and lifestyle modifications are essential to enhance recovery and redefine postoperative management in gastric cancer patients.

Key Words: Gut microbiota; Probiotics; Postoperative depression; Gastric cancer; Psychotropic therapy; Holistic recovery

Core Tip: Post-gastric cancer surgery, depression critically impacts recovery. Combining Bifidobacterium triple viable bacteria with mirtazapine reduced Self-Rating Depression Scale depression scores by 32%, improved neuroendocrine markers, and modulated gut microbiota. Integrating these interventions with psychological support and lifestyle changes optimizes patient adaptation and long-term well-being.

TO THE EDITOR

Gastric cancer is among the most formidable malignancies globally, with radical surgery constituting a cornerstone of curative treatment[1]. However, the physical and psychological sequelae of such procedures often extend beyond the immediate postoperative period. Postoperative depression, a frequently underdiagnosed condition, has emerged as a significant impediment to recovery, adversely affecting both physical rehabilitation and overall quality of life[2]. Critically, current management strategies for postoperative depression remain limited by three key gaps: Existing antidepressant therapies primarily target symptoms while neglecting the underlying gut dysbiosis, characterized by an imbalance in gut microbial composition with a significant reduction in beneficial bacteria populations; clinical guidelines lack standardized approaches for microbiota modulation despite compelling evidence of the gut-brain axis's role in depression pathogenesis; the integration of microbiota-targeted therapy into surgical recovery represents an innovative approach, although current evidence remains limited by small-scale studies and undefined optimal protocols. While promising enhanced postoperative mental health, its clinical adoption requires further validation through large, controlled trials assessing both efficacy and surgical-specific outcomes[3].

Recent advancements in understanding the gut-brain axis have not only illuminated the microbiota's role in mental health but also highlighted this gap between mechanistic knowledge and clinical translation. Lu et al’s study[4] directly addresses this unmet need by investigating Bifidobacterium triple viable bacteria as an adjunct to mirtazapine therapy—a dual-target strategy designed to simultaneously ameliorate depressive symptoms and restore gut-ecosystem balance, thereby offering a more comprehensive approach to postoperative depression management.

The gut-brain axis and postoperative depression

The gut-brain axis represents a bidirectional communication network linking the central nervous and enteric nervous systems, with the vagus nerve serving as a critical anatomical and functional conduit. The gut microbiota plays a pivotal role in this axis by producing neurotransmitters, modulating immune responses, and regulating systemic inflammation. Dysbiosis has been strongly implicated in depression pathogenesis[5,6]. Following gastric cancer surgery, multiple iatrogenic factors exacerbate this relationship: Vagal nerve damage during gastrectomy disrupts gut-brain signaling, impairing microbiota-modulated neurotransmitter production; anatomical alterations (e.g., reduced gastric acid secretion) permit pathogenic bacterial overgrowth; postoperative antibiotic use further depletes commensal species like Bifidobacterium[7]. These surgical sequelae create a self-perpetuating cycle where dysbiosis worsens depression, which in turn exacerbates gut dysfunction through stress-mediated pathways. The study by Lu et al[4] demonstrated that Bifidobacterium triple viable bacteria not only restores microbial balance but may also compensate for vagal disruption by directly producing neuroactive metabolites. This synergistic approach both alleviates depressive symptoms and promotes gut health, highlighting the interconnectedness of mental and physical well-being.

Mechanisms by which the gut microbiota influences mental health

The gut microbiota influences mental health through several mechanisms, which collectively contribute to the regulation of mood, stress response, and cognitive function. Bifidobacterium longum R0175 and Lactobacillus helveticus R0052 have demonstrated particular efficacy in mental health applications through multiple validated pathways: Production of gamma-aminobutyric acid (GABA) and other neuroactive metabolites that directly modulate central nervous system activity; regulation of circulating pro-inflammatory cytokines that impact hippocampal neurogenesis; enhancement of intestinal barrier integrity, reducing endotoxin-mediated neuroinflammation. Clinical studies have demonstrated that these strains can reduce depressive symptoms by 28%-42% compared to placebo, while also showing superior colonization resistance against pathogens and promoting beneficial commensals. However, translation to clinical practice faces challenges including: High cost of microbiome analysis for specific strains; viability of probiotics in commercial formulations varies, and improved stabilization techniques may help overcome these barriers. The significant clinical benefits - including not only mood improvement but also reduced systemic inflammation and enhanced treatment adherence rates-suggest these psychobiotics could transform postoperative mental health management despite current implementation challenges[8-10].

Neurotransmitter production: Gastrointestinal bacteria produce neurotransmitters such as serotonin, dopamine, and GABA, which are critical for mood regulation. Approximately 90% of serotonin, a neurotransmitter associated with feelings of well-being and happiness, is produced in the gastrointestinal tract[11-13]. Dysbiosis can disrupt this production, leading to mood disorders. For example, reduced serotonin levels have been linked to increased anxiety and depression, whereas imbalances in GABA production can impair stress resilience[14].

Immune system modulation: The gut microbiota modulates the immune system, thereby influencing systemic inflammation, which has been linked to depression. Chronic inflammation can promote the release of pro-inflammatory cytokines that affect brain function and contribute to depressive symptoms. For instance, elevated levels of interleukin-6 and tumor necrosis factor-alpha have been associated with increased depressive behaviors in both animal models and human studies[15,16].

Vagal nerve signaling: The vagus nerve transmits signals from the gastrointestinal tract to the brain, influencing emotional regulation and stress responses. Disruptions in this pathway, often caused by microbial imbalances, can lead to heightened stress sensitivity and mood instability[17,18]. Dysbiosis can impair vagal signaling, further exacerbating mood disturbances.

These mechanisms highlight the importance of gut microbiota health for mental well-being, particularly in the context of postoperative recovery. Understanding these pathways provides a foundation for developing targeted interventions to alleviate postoperative depression.

Therapeutic implications and multidisciplinary care

The integration of probiotics with psychotropic therapy offers a promising approach for managing postoperative depression, with clinical studies demonstrating enhanced efficacy when combining specific Bifidobacterium strains with mirtazapine[19]. However, important safety considerations regarding potential gut-mediated alterations of drug metabolism and strain-specific effects on neurotransmitter systems must be carefully evaluated through systematic pharmacokinetic studies. These biological interactions highlight the need for comprehensive safety monitoring alongside efficacy assessments. When implemented within a holistic care framework that simultaneously addresses psychological wellbeing through cognitive behavioral therapy and social support systems, this microbiota-targeted strategy may offer a more complete therapeutic solution while mitigating potential risks.

Early screening and diagnosis: Early identification of depressive symptoms using standardized screening tools such as the Patient Health Questionnaire-9 is crucial. Routine screening should be incorporated into postoperative follow-up protocols to enable timely intervention. Early detection permits the implementation of preventive measures, reducing the risk of severe depressive episodes and improving overall recovery outcomes[20].

Pharmacological interventions: The combination of probiotics and psychotropic medications, as demonstrated by Lu et al[4], offers a potentially synergistic approach to alleviating depressive symptoms, although clinical outcomes have shown variability across studies. While certain Bifidobacterium and Lactobacillus strains have demonstrated capacity to enhance antidepressant efficacy in some trials, meta-analyses note significant interstudy heterogeneity with approximately 35% of randomized controlled trials showing null effects on mood outcomes[21]. The most consistent benefits appear in populations with confirmed gut dysbiosis, where probiotic-psychotropic combinations have shown dual improvement in both depressive symptoms and gastrointestinal health markers. This suggests that the therapeutic potential may depend on careful patient stratification and strain selection, emphasizing the need for precision in microbiota-targeted interventions (Table 1).

Table 1 Integrated probiotic-antidepressant treatment protocol.

Phase	Timeline	Intervention components	Clinical and microbiome monitoring	Quality control measures
Preoperative baseline	2 weeks pre-surgery	Comprehensive gut microbiome profiling (targeted 16S rRNA sequencing). Standardized psychometric assessment (HAMD-17, SDS). Nutritional status evaluation	Alpha/Beta diversity indices. Baseline depression severity. Serum inflammatory markers (interleukin-6 and C-reactive protein)	Standardized stool collection protocol. Blind-rated psychological assessments
Perioperative initiation	Day 0-1 (surgery)	Single-dose probiotic loading (B. longum R0175 2 × 109 CFU). Anesthesia protocol optimization (vagus nerve-sparing techniques)	Surgical stress biomarkers (cortisol, norepinephrine). Acute pain scores	Probiotic viability testing. Surgical team training
Active treatment	Weeks 1-8 post-op	Pharmacotherapy: Mirtazapine titration (15→30 mg/day); Bifidobacterium triple viable (2 g bid). Adjuncts: Weekly cognitive behavioral therapy sessions; Mediterranean diet protocol	Weekly: Depression scales (HAMD/SDS), gastrointestinal symptom diary. Biomarkers: Monthly serum brain-derived neurotrophic factor, serotonin; Stool microbiome (Weeks 4,8)	Pharmacy-compounded probiotics. Medication adherence monitoring
Maintenance and transition	Months 3-6	Probiotic tapering (50% dose reduction monthly). Monthly booster psychotherapy. Personalized exercise prescription	3-month microbiome stability. Quality of life (EORTC QLQ-C30). Depression relapse rates	Telehealth follow-ups. Digital symptom tracking

HAMD-17: Hamilton Rating Scale for Depression; SDS: Self-Rating Depression Scale.

Psychological support: Psychological interventions, including cognitive–behavioral therapy and mindfulness-based stress reduction, effectively reduce depressive symptoms and improve quality of life. Support groups and counseling can also enhance emotional resilience in patients managing the challenges of cancer diagnosis and surgery. These interventions help patients develop coping strategies, improve emotional regulation, and foster a sense of community and support[22,23].

Dietary optimization: Nutritional interventions play vital roles in supporting gastrointestinal health. Fiber-rich diets, such as the Mediterranean diet, promote the growth of beneficial gastrointestinal bacteria[24]. Prebiotics, which serve as food for probiotics, can further enhance microbial balance[25]. Additionally, reducing the intake of processed foods and sugars can help prevent dysbiosis and support a healthy gastrointestinal environment.

Lifestyle modifications: Regular physical activity, including aerobic exercises and yoga, has been found to improve mood and reduce stress. Stress management techniques, such as meditation and deep breathing exercises, can also contribute to mental well-being[26,27]. These lifestyle changes both support mental health and enhance physical recovery, creating a holistic approach to postoperative care.

Clinical evidence supporting the use of probiotics

Several clinical studies have demonstrated the benefits of probiotics in managing depression. For instance, a randomized controlled trial involving patients with major depressive disorder found that the combination of Lactobacillus and Bifidobacterium strains significantly reduced depressive symptoms vs placebo[28]. Another study highlighted that probiotics could enhance the efficacy of antidepressants, reducing the required dosage and minimizing side effects[29]. These findings align with those of Lu et al[4], who revealed that Bifidobacterium triple viable bacteria-assisted mirtazapine therapy significantly improved depressive symptoms in patients after gastric cancer surgery. These studies collectively underscore the potential of probiotics as adjunctive therapies for managing postoperative depression.

Future direction

The emerging field of microbiota-targeted therapy holds immense potential for revolutionizing postoperative care in patients with gastric cancer[30]. Future research should focus on several key areas to fully realize this potential.

Elucidating mechanisms: Further research is needed to understand the specific mechanisms by which the gut microbiota influences mental health. This includes exploring the roles of microbial metabolites, immune modulation, and neural signaling pathways[31-33]. A deeper understanding of these mechanisms will enable the development of more targeted and effective interventions.

Personalized probiotic formulations: Advances in microbiome sequencing technologies could enable the development of personalized probiotic formulations based on individual gut microbiota profiles[34]. This tailored approach could enhance treatment efficacy and reduce adverse effects. Personalized medicine and microbiota-targeted therapies represent the future of healthcare.

Large-scale clinical trials: Large-scale, randomized controlled trials are needed to validate the efficacy and safety of probiotic-psychotropic combinations. These trials should also explore the long-term effects of microbiota-targeted therapies on mental health and recovery. Robust clinical evidence will be essential for integrating these therapies into standard care protocols.

Integration with emerging therapies: The potential of combining probiotics with other emerging therapies, such as immunotherapy and targeted drug delivery systems, should be investigated[35]. For example, probiotics could enhance the efficacy of immune checkpoint inhibitors by modulating the tumor microenvironment[36]. Exploring these synergies could open new avenues for comprehensive cancer care.

CONCLUSION

Postoperative depression is a significant but often neglected complication of gastric cancer surgery, possessing profound implications for patient recovery. The gut-brain axis offers a novel framework for understanding and addressing this condition, with probiotics and psychotropic medications serving as complementary therapeutic tools. By adopting a multidisciplinary and personalized approach to care, clinicians can enhance mental well-being, improve quality of life, and optimize long-term outcomes for patients with gastric cancer. The integration of microbiota-targeted therapy into postoperative care represents a paradigm shift, underscoring the importance of holistic recovery-comprehensive healing addressing biological, psychological and social factors- in modern oncology.