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New perspectives on microbiome-dependent gut-brain pathways for the treatment of depression with gastrointestinal symptoms: from bench to bedside.
Patients with depression are more likely to have chronic gastrointestinal (GI) symptoms than the general population, but such symptoms are considered only somatic symptoms of depression and lack special attention. There is a chronic lack of appropriate diagnosis and effective treatment for patients with depression accompanied by GI symptoms, and studying the association between depression and GI disorders (GIDs) is extremely important for clinical management. There is growing evidence that depression is closely related to the microbiota present in the GI tract, and the microbiota-gut-brain axis (MGBA) is creating a new perspective on the association between depression and GIDs. Identifying and treating GIDs would provide a key opportunity to prevent episodes of depression and may also improve the outcome of refractory depression. Current studies on depression and the microbially related gut-brain axis (GBA) lack a focus on GI function. In this review, we combine preclinical and clinical evidence to summarize the roles of the microbially regulated GBA in emotions and GI function, and summarize potential therapeutic strategies to provide a reference for the study of the pathomechanism and treatment of depression in combination with GI symptoms.
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Lacticaseibacillus rhamnosus KY16 Improves Depression by Promoting Intestinal Secretion of 5-HTP and Altering the Gut Microbiota.
Increasing research suggests a connection between gut microbiota and depressive disorders. Targeted changes to the intestinal flora may contribute to alleviating anxiety and depression. This study aimed to identify probiotics that could attenuate stress-induced abnormal behavior and explore potential mechanisms. The administration of LR.KY16 significantly reduced stress-induced abnormal behaviors and physiological dysfunction. The mechanism may be via regulating the structure of the intestinal microbiota in mice, increasing the abundance of Akkermansia muciniphila, prompting enterochromaffin cells to secrete 5-HTP in the gut, which enters the brain through the bloodstream and promotes the synthesis of 5-HT in the brain, and then activates brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) through the 5-HT1A receptor. In addition, LR.KY16 also increased the expression of claudin-7, occludin, and zonula occludens-1 (ZO-1) in the colon, inhibited microglial M1 polarization, and inhibited systemic inflammation.
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Compound Lactic Acid Bacteria Alleviate Metabolic Dysregulation in Rhesus Macaques with Chronic Restraint Stress Via Remodeling the Gut Microbiota.
Chronic stress is a critical risk factor for depression, and prolonged exposure to stressors increases the risk of metabolic dysregulation. Gut microbiota (GM) intervention is a promising therapeutic target for stress-related emotional and behavioral disorders. In the present study, we apply compound lactic acid bacteria (CLAB) (Lacticaseibacillus rhamnosus GG and Enterococcus faecium) administration therapy to investigate the effect of gut microbiota (GM) on chronic restraint stress (CRS)-depression and its related glucose-lipid metabolism disturbance. We established a non-human primate model of CRS depression to mimic the depressive state in humans and applied CLAB for gastric gavage treatment. CRS macaques exhibit marked depressive-like behavior and disrupted GM structure, decreased levels of C1q/tumor necrosis factor-related protein 9 (CTRP9) and increased levels of CTRP5, and induced insulin resistance (IR) and lipid metabolism disorders. Treatment with CLAB normalized GM structure in CRS macaques, increased the abundance of Lactobacillus murinus and Lactobacillus reuteri, and reduced depressive-like behavior in CRS macaques, with a rebound in CTRP9 and HDL-C levels, reduced CTRP5 and TG levels and improved IR. In addition, CLAB may serve as a promising non-pharmacological intervention that alleviates depression-related metabolic dysregulation by modulating the gut microbiota and improving lipid and glucose metabolism.
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Multi-kingdom microbiota analysis reveals bacteria-viral interplay in IBS with depression and anxiety.
Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder frequently accompanied by psychological symptoms. Bacterial microbiota plays a critical role in mediating local and systemic immunity, and alterations in these microbial communities have been linked to IBS. Emerging data indicate that other intestinal organisms, including bacteriophages, are closely interlinked with the bacterial microbiota and their host, yet their collective role remains to be elucidated. Here, we analyze the gut multi-kingdom microbiota of 360 IBS patients from a prospective cohort study in Hong Kong, with participants phenotyped through psychological assessment. Our findings reveal significantly lower intra-community correlations in IBS patients compared to healthy controls and highlight unique taxa patterns associated with IBS and mental disorders. Utilizing multi-omic data alongside machine learning techniques, we successfully predicted psychiatric comorbidities in IBS, achieving an average AUC of 0.78. Notably, gut viruses emerged as significant contributors to our predictive model, indicating a vital role for bacteriophages in the gut microbiome of IBS patients. We found that lysogenic phages in IBS displayed a broader host range, with Bilophia containing the most abundant prophages. Our analysis further indicates that IBS patients with depression exhibited a higher prevalence of viral-encoded auxiliary metabolic genes, specifically those involved in the sulfur metabolic pathway related to ubiquinone biosynthesis. The gut virome is increasingly reported to play an important role in the pathogenesis of many diseases. The study provides a systematic characterization of the drivers of the gut viral community and further expands our knowledge of the distinct interaction of gut viruses with their prokaryotic hosts, which is critical for understanding the viral-bacterial environment in IBS.
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Is there a causal link between psychological disorders and functional gastrointestinal disorders?
INTRODUCTION: Psychological distress is associated with functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS) and functional dyspepsia (FD) but only evidence from prospective longitudinal and treatment studies can indicate whether the link between FGIDs and psychological distress is causal. Emerging evidence suggests underlying biological mechanisms may explain the association of psychological distress with FGIDs. AREAS COVERED: This review critically evaluates whether anxiety and/or depression and FGIDs are causally related including evidence for a temporal sequence, strength and specificity of the association, biological gradient, and biological plausibility. EXPERT OPINION: Accumulating evidence suggests that psychological factors are causal for symptoms in a subset of FGID patients and not explained by health care seeking behavior (brain-gut disorder). In other cases, psychological factors may arise secondary to intestinal disease (gut-brain disorder). Prospective population-based studies are needed in FGIDs other than IBS and FD to determine if a similar brain-gut and gut-brain syndrome exists. Treatment studies have not phenotyped FGIDs according to brain-gut versus gut-brain origins which may be important in understanding true treatment efficacy. Future research needs to unravel biological mechanisms that may explain the link between psychological factors and FGIDs but promising data in the area of the brain-gut-immune-microbe axis is emerging.
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Psychological stress and immune dysregulation: Insights from neuroimmunology and the gut-brain-immune axis.
The interplay between mental health, immune function, and gut microbiota has garnered increasing attention in recent years, with mounting evidence indicating that psychological stress and depression are increasingly associated with alterations in immune responses and systemic health. Chronic stress and depression are closely associated with immune dysregulation and have been implicated in the onset and progression of autoimmune diseases, cardiovascular disorders, cancer, and other inflammation-related conditions，although these relationships are complex and not strictly causal. Emerging research highlights the gut-brain-immune axis as a critical mediator of these effects, where alterations in gut microbiota composition, microbial metabolites, and intestinal barrier integrity modulate systemic inflammation, immune cell function, and neural activity. This review examines the intricate relationship between depression, stress, immune dysregulation, and gut microbiota, focusing on how psychological states are associated with changes in immune markers, inflammatory pathways, and cellular immunity. We discuss the roles of key neural systems, including prefrontal-limbic circuits and brainstem-autonomic pathways, in shaping immune-related processes, the influence of neurotransmitters including serotonin and norepinephrine, and the impact of autonomic nervous system activity on immune modulation. Furthermore, we explore how gut microbial dysbiosis and microbial metabolites contribute to neuroimmune interactions, providing novel insights into the mechanisms linking psychological and immune health. By synthesizing current evidence, this review underscores the potential for integrated therapeutic strategies that simultaneously target mental health, immune function, and gut microbiota, and highlights avenues for future research in psychoneuroimmunology and clinical translation.
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Differential effects of prenatal depression and anxiety on infant sleep: dual-pathway mechanisms involving the hypothalamic-pituitary-adrenal axis and the gut-brain axis.
STUDY OBJECTIVES: Prenatal psychological distress is associated with adverse offspring outcomes, including infant sleep disturbances (ISD) and altered gut microbiota, yet the mediating roles of the neonatal gut microbiome and tryptophan metabolism remain underexplored. MATERIALS AND METHODS: This prospective birth cohort study enrolled 2288 mother-infant pairs, using questionnaires to assess prenatal anxiety/depression and infant sleep patterns up to 12 months. A 112-pair sub-cohort underwent multi-omics analyses: meconium microbiota profiling via 16S rRNA sequencing and cord blood tryptophan metabolite quantification via liquid chromatography-tandem mass spectrometry. Least absolute shrinkage and selection operator (LASSO) regression, mediation analyses, and XGBoost modeling were applied. RESULTS: Prenatal depression alone was a significant risk factor for ISD (fully adjusted OR = 1.53, 95% CI: 1.04-2.25), with a stronger effect in female infants (OR = 2.11, p = .022). Cord blood cortisol partially mediated this link (Average Causal Mediation Effect = -7.47, 95% CI: [-14.82, -0.12], p = .048). Prenatal anxiety correlated with reduced meconium microbial alpha-diversity, lower Bifidobacterium abundance, and decreased 3-HAA/serotonin levels, which were associated with sleep disturbance; serial mediation confirmed the gut microbiota-tryptophan metabolism pathway. The XGBoost predictive model achieved an AUC of 0.727, with microbial diversity, Streptococcus abundance, dopamine, and 3-HAA as top contributors. CONCLUSIONS: This study identifies distinct mediating pathways for depression and anxiety, providing targets for personalized infant sleep health interventions. Statement of Significance This study reveals that prenatal depression and anxiety impair infant sleep through distinct biological pathways. Depression was associated with elevated fetal cortisol (HPA axis), while anxiety may influence the neonatal gut microbiome and its production of sleep-regulating tryptophan metabolites. These findings contribute to a novel dual-pathway model that helps clarify previously unresolved mechanistic questions. By integrating these biomarkers into a machine learning model, we offer a translational tool for early risk prediction. The work bridges a critical gap between epidemiological observation and biological mechanism, paving the way for personalized interventions-targeting stress hormones for depression or gut health for anxiety-to improve infant neurodevelopmental outcomes.
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Social stress-induced depressive-like symptoms and changes in gut microbial and lipidomic profiles are prevented by pharmacological inhibition of FAAH activity in male rats.
Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity has antidepressant-like effects in preclinical models of stress. In this study, we investigated whether the antidepressant-like effects of FAAH inhibition are associated with corresponding changes in gut microbial and lipidomic profiles, which are emerging as critical components in the pathophysiology of depression. Adult male Wistar rats experienced five weeks of repeated social defeat or control procedure and were treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle starting from the third week. Repeated social defeat induced the emergence of depressive-like behavioral (sucrose preference reduction and passive coping behaviors in the forced swim test) and neuroendocrine (increased corticosterone levels) changes, which were prevented by URB694 treatment. Repeated social defeat also provoked a significant variation in gut microbiota (changes in the relative abundance of 14 bacterial taxa) and lipidic (e.g., glycerophospholipids) composition. These stress-induced changes were prevented by URB694 treatment. These findings indicate that inhibition of FAAH activity with URB694 blocks the co-occurrence of depressive-like behavioral and neuroendocrine changes and alterations in gut microbial and lipid composition in rats exposed to repeated social defeat. In conclusion, these results suggest that the gut microbiota-lipid crosstalk may represent a novel biological target for FAAH inhibitors to enhance stress resilience.
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[Intestinal microbiota and the brain: multilevel interactions in health and disease].
Commensal bacteria of the digestive tract are separated from the brain by multiple barriers. Despite that bacteria residing in the intestine and the neurons of the brain interact by neural and humoral pathways. Mental processes, such as the stress response, may affect the composition and function of intestinal bacteria via the brain-gut axis. On the other hand, intestinal bacteria can influence the processes in the brain through the gut-brain axis. Disruption of these interactions may be involved in various alterations both in the function of the gastrointestinal tract and the brain function.
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Sotagliflozin attenuates cardiac dysfunction and depression-like behaviors in mice with myocardial infarction through the gut-heart-brain axis.
Myocardial infarction (MI) and depression are leading causes of mortality and morbidity globally, and these conditions are increasing recognized as being fundamentally interconnected. The recently recognized gut-heart-brain axis offers insights into depression following MI, but effective treatments for this comorbidity remain lacking. To address this medical need, we employed an animal model of MI to investigate the potential repurposing of sotagliflozin (SOTA), an approved sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor for diabetes, for managing depression following MI and identifying potential SOTA-associated microbial mechanisms. SOTA treatment improved cardiac dysfunction and alleviated depression-like behaviors induced by MI, accompanied by alterations in gut microbiota composition, such as changes in the Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001. Moreover, fecal microbiota transplantation (FMT) using fecal samples from SOTA-treated MI mice demonstrated that gut microbiota contributed to the beneficial effects of SOTA on cardiac dysfunction and depression-like behaviors in MI mice. Intriguingly, FMT-based intervention and concordance analysis of gut microbiota before and after FMT suggested that Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001 were associated with the beneficial effects of SOTA. Furthermore, functional prediction of gut microbiota and correlation analysis support the significance of these dynamic microbial communities. In conclusion, these findings suggest that SOTA could serve as a potential drug to ameliorate cardiac dysfunction and depressive symptoms in MI patients via through the gut-heart-brain axis.