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Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice.
Gut microbiome is implicated in the onset and progression of major depressive disorder (MDD), but the dynamic alterations of depressive symptoms, gut microbiome, and fecal metabolome across different stages of stress exposure remain unclear. Here, we modified the chronic social defeat stress (CSDS) model to evaluate mice subjected to social defeat stress for 1, 4, 7, and 10 days. Behavioral tests, 16S rRNA, metagenomics, and fecal metabolomics were conducted to investigate the impact of stress exposure on behaviors, gut microbiota and fecal metabolites. We observed that depressive-like behaviors, such as anhedonia and social avoidance, worsened significantly as stress exposure increased. The microbial composition, function, and fecal metabolites exhibited distinct separations across the different social defeat stress groups. Mediation analysis identified key bacteria, such as Lachnospiraceae_UCG-001 and Bacteroidetes, and fecal metabolites like valeric acid and N-acetylaspartate. In our clinical depression cohort, we confirmed that fecal valeric acid levels, were significantly lower in depressive-like mice and MDD patients, correlating closely with stress exposure and anhedonia in mice. Further analysis of serum and brain metabolites in mice revealed sustained changes of N-acetylaspartate abundance in fecal, serum, and cortical samples following increasing stress exposure. Together, this study elucidated the characteristics of depressive-like behaviors, gut microbiome, and fecal metabolome across various social defeat stress exposure, and identified key bacteria and fecal metabolites potentially involved in modulating social defeat stress response and depressive-like behaviors, providing new insights into the pathogenesis and intervention of depression.
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Lignans Alleviate Depression by Modulating the Gut-Brain Axis: Effect and Mechanism Based on Multi-Omics Analyses.
Major depressive disorder (MDD) is a highly disabling psychiatric illness characterized by persistent low mood and psychomotor retardation, often leading to cognitive impairment or even suicidality. As the pathogenesis remains poorly understood, the currently available treatment regimens are mostly symptomatic therapies with little satisfactory curative effect. The emerging paradigm of gut-brain axis has highlighted gut dysbiosis as a key etiological factor to elicit neuro-inflammation and jeopardize the central nervous system homeostasis. In this study, we evaluated the ameliorating effects of flaxseed lignans on the gut microbiome to regain the gut micro-environmental functionality and alleviate MDD. The lignans significantly mitigated the severity of disease and markedly altered the gut microbiota structure in the participants. In the MDD mouse model, the lignans reversed the experimental depression-like behaviors, repaired neural and gut damage and restored barrier integrity. Of great significance, the lignans elevated the levels of 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA), and markedly attenuated microglial and systemic inflammation. Mechanistically, the lignans inhibited the IL-17/AP-1/NF-κB axis through direct interaction with the Fos protein. In the BV-2 cells, the lignan enterolactone reduced levels of nitric oxide and pro-inflammatory cytokines, further validating the anti-inflammatory mechanism of the lignans. Together, these findings demonstrate that lignans exert potent antidepressant effects by modulating the gut-brain axis and resolving neuro-inflammation, providing useful information for the development of novel therapeutic strategies for MDD prevention and treatment.
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[Gut microbiome and major depressive disorder : The other side of ourselves].
Microbiological ecology and its ambition to describe the complete genome of complex living communities as a whole, have given us powerful tools to characterize the human gut microbiome on a genetic and, hence, taxonomic and abundance level; for a decade now, they have become sufficiently inexpensive, fast and feasible. Thus, opportunities arose to have a fresh and closer look at the microbiota-gut-brain-axis and its impact on human health; this axis comprises a complex multisystemic network of multidirectional interactions between brain and gut including influences beyond one generation. Gnotobiotic animal models have become essential for specific research targets. Combining gut microbiome analysis with observations on the hypothalamus-pituitary-adrenal axis and various aspects of inflammation helped to gain first insights into the role of the microbiota-gut-brain-axis in depressive disorders. Therapeutic endeavors with psychobiotics have not yet shown their value in clinical studies.
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Dihydroartemisinin Protects Mice from CUMS-induced Depression-like Behaviors by Regulating Gut Microbes.
Depression is one of the most common forms of psychopathology, which is associated with gut microbiota dysfunction. Dihydroartemisinin (DHA) has been shown to regulate gut microbiota and ameliorate neuropathies, but whether it can be used to treat depression remains unclear. Our study found that DHA treatment raised the preference for sugar water in chronic unpredictable mild stress (CUMS)-induced mice and reduced the immobility time in open field, forced swimming and tail suspension experiments, and promoted doublecortin expression. Additionally, DHA up-regulated the diversity and richness of intestinal microbiota in depression-like mice, and restored the abnormal abundance of microbiota induced by CUMS, such as Turicibacter, Lachnospiraceae, Erysipelotrichaceae, Erysipelatoclostridium, Eubacterium, Psychrobacter, Atopostipes, Ileibacterium, Coriobacteriacea, Alistipes, Roseburia, Rikenella, Eggerthellaceae, Ruminococcus, Tyzzerella, and Clostridia. Furthermore, KEGG pathway analysis revealed that gut microbiota involved in the process of depression may be related to glucose metabolism, energy absorption and transport, and AMPK signaling pathway. These results indicated that DHA may play a protective role in CUMS-induced depression by mediating gut-microbiome.
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Exploring the mechanisms of action of probiotics in depression: Results from a randomized controlled pilot trial.
BACKGROUND: We previously reported greater reductions in depression and anxiety following probiotic supplementation in people with major depressive disorder (MDD) in a randomised double-blind placebo-controlled pilot trial (Nikolova et al., 2023). Here, we investigate the mechanisms underlying these effects. METHODS: 49 people with MDD received a multi-strain probiotic (n = 24) or placebo (n = 25) for 8 weeks in addition to their antidepressant. Stool and blood samples were collected to analyse gut microbiota composition and inflammatory cytokines. Stool samples from 25 matched healthy volunteers (HVs) were also obtained. RESULTS: Within the probiotic group, there was a significant increase in richness according to Chao1(bias-corrected) (w4 p = 0.04) and a trend for increased Total count (w4 p = 0.06, w8 p = 0.09) compared to baseline, but not to placebo. When compared to HVs post-treatment, only the placebo group had a significant decrease in Shannon' entropy (p = 0.03) and a trend for decreased Total count (p = 0.08) and Simpson's index (p = 0.09). Between-group differences in beta diversity were observed at week 4 (p = 0.04), but not week 8. Consistent between-group differences were seen in family Bacilleceae post-treatment (FDR p < 0.05), which correlated with decreases in anxiety (FDR p < 0.05). There were no differences in inflammatory markers. LIMITATIONS: This study was limited by data loss during the COVID-19 Pandemic. CONCLUSION: Probiotics may positively impact the microbiota by normalising diversity and increasing levels of health-related taxa, which may partially account for their benefits in MDD. Understanding how these changes relate to symptom improvement can inform their targeted use in clinical practice. Larger trials incorporating functional multi-omics are needed. TRIAL REGISTRATION: NCT03893162.
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Finding intestinal fortitude: Integrating the microbiome into a holistic view of depression mechanisms, treatment, and resilience.
Depression affects at least 322 million people globally, or approximately 4.4% of the world's population. While the earnestness of researchers and clinicians to understand and treat depression is not waning, the number of individuals suffering from depression continues to increase over and above the rate of global population growth. There is a sincere need for a paradigm shift. Research in the past decade is beginning to take a more holistic approach to understanding depression etiology and treatment, integrating multiple body systems into whole-body conceptualizations of this mental health affliction. Evidence supports the hypothesis that the gut microbiome, or the collective trillions of microbes inhabiting the gastrointestinal tract, is an important factor determining both the risk of development of depression and persistence of depressive symptoms. This review discusses recent advances in both rodent and human research that explore bidirectional communication between the gut microbiome and the immune, endocrine, and central nervous systems implicated in the etiology and pathophysiology of depression. Through interactions with circulating inflammatory markers and hormones, afferent and efferent neural systems, and other, more niche, pathways, the gut microbiome can affect behavior to facilitate the development of depression, exacerbate current symptoms, or contribute to treatment and resilience. While the challenge of depression may be the direst mental health crisis of our age, new discoveries in the gut microbiome, when integrated into a holistic perspective, hold great promise for the future of positive mental health.
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The human gut microbiota and depression: widely reviewed, yet poorly understood.
BACKGROUND: A large number of existing reviews have discussed the role of the gut microbiota in affective disorders, though syntheses have been overwhelmingly narrative in their focus. METHOD: In this correspondence, we compliment Sanada et al. (2020) on their recent systematic review of the gut microbiota in Major Depressive Disorder (MDD), the first to incorporate a meta-analysis. We also comment on how this synthesis should be extended in future research. RESULTS: Sanada et al. (2020) conducted a meta-analysis of alpha diversity in participants with MDD compared to controls, whereby they unexpectedly observed no significant difference between groups. A meta-analysis was only able to be performed on alpha diversity indices. Future research should consider research quality, other forms of depression, incorporate comprehensive meta-analyses, where possible, as well as investigate associations between anxiety/depression symptom measures and the gut microbiota. LIMITATIONS: Further consideration of papers which incorporate functional analyses (e.g., metabolomics) is required to integrate this body of literature. CONCLUSIONS: Research investigating the microbiota-gut-brain axis in affective disorders has been met with great enthusiasm, offering promising direction for novel therapeutics in conditions such as depression. We encourage further systematic reviews in this space, particularly which consider research quality and incorporate comprehensive meta-analyses.
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Adjunctive fecal microbiota transplantation for major depressive disorder: A randomized, double-blind, placebo-controlled trial.
Gut microbiota may influence antidepressant treatment outcomes, yet whether targeted modulation can enhance efficacy remains unclear. We conducted a randomized, double-blind, placebo-controlled trial in patients with major depressive disorder, administering a 2-week course of fecal microbiota transplantation (FMT) capsules or placebo as an adjunct to escitalopram (ChiCTR2300071421). Remission rates at week 8 did not differ significantly between groups, but FMT produced greater reductions in Hamilton Depression Rating Scale, 17-item version (HAMD-17) scores at weeks 2 and 8. FMT was well-tolerated with a safety profile comparable to placebo. Multi-omics analyses show durable donor microbial engraftment and enrichment of beneficial Lachnospiraceae and Oscillospiraceae taxa. Microbial remodeling is accompanied by an increase in serum bile acids that correlate with the alleviation of depressive symptoms. Mediation analysis supports a bile-acid-mediated suppression of inflammatory pathways linking microbial changes to antidepressant effects. Overall, FMT may provide a safe avenue to enhance escitalopram efficacy through microbiota-directed regulation of bile-acid metabolism and inflammation.
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The role of gut microbiota in adolescent depression: Insights from adverse childhood experiences.
BACKGROUND: Depression has become a leading global mental health disorder, with a rising prevalence of 15-20 % among adolescents. Emerging evidence suggests that adolescent depression may constitute a distinct subtype, differing clinically and neurobiologically from adult presentations. The gut microbiota's role in psychiatric disorders has garnered increasing attention, as dysbiosis may modulate behavior and mood via the microbiota-gut-brain axis, potentially contributing to depressive pathogenesis. METHODS: This study included 60 depressed and 64 healthy adolescents (aged 11-18). Fecal samples were immediately flash-frozen in liquid nitrogen after collection, stored at -80 °C within 30 min, and processed within 6 months to minimize DNA degradation. And microbial DNA was extracted using the HiPure Stool DNA Mini Kit. The V3-V4 hypervariable regions of the 16S rRNA gene were amplified via PCR with primers 341F (5'-CCTAYGGGRBGCASCAG-3') and 805R (5'-GACTACHVGGGTATCTAATCC-3'), followed by Illumina NovaSeq 6000 sequencing. PCR cycle optimization was performed via gradient testing (20-30 cycles), confirming 25 cycles as optimal to prevent chimera formation while maintaining amplicon yield. Bioinformatics pipelines included QIIME2 for quality filtering, DADA2 for ASV inference, and PICRUSt2 for functional prediction. Statistical analyses included t-tests, mediation analysis, and Linear discriminant analysis Effect Size (LEfSe). RESULTS: Fifty percent of depressed adolescents originated from single-parent or grandparent-led households and exhibited reduced resilience scores alongside elevated adverse childhood experiences (ACEs). Gut microbiota analysis revealed significant compositional and functional dysbiosis in depressed youth, marked by depletion of beneficial taxa (e.g., Bifidobacterium, Faecalibacterium) and butyrate-producing species, alongside enrichment of pro-inflammatory genera (e.g., Escherichia-Shigella). Mediation analyses implicated ACEs as a potential driver of these microbial alterations. CONCLUSIONS: This study reveals distinct gut microbiota profiles in adolescents with depression compared to healthy controls, offering mechanistic insights into how ACEs and microbial dysbiosis may contribute to depressive etiology.
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Fermented foods, the gut and mental health: a mechanistic overview with implications for depression and anxiety.
Mental disorders including depression and anxiety are often comorbid with gut problems, suggesting a bidirectional relationship between mental health and gut function. Several mechanisms might explain this comorbidity, such as inflammation and immune activation; intestinal permeability; perturbations in the hypothalamic-pituitary-adrenal axis; neurotransmitter/neuropeptide dysregulation; dietary deficiencies; and disturbed gut microbiome composition. The potential of modulating the microbiome-gut-brain axis, and subsequently mental health, through the use of functional foods, is an emerging and novel topic of interest. Fermented foods are considered functional foods due to their putative health benefits. The process of microbial fermentation converts food substrates into more nutritionally and functionally rich products, resulting in functional microorganisms (probiotics), substrates that enhance proliferation of beneficial bacteria in the gut (prebiotics), and bioactive components (biogenics). These functional ingredients act biologically in the gastrointestinal tract and have the ability to modify the gut microbiota, influence translocation of endotoxins and subsequent immune activation, and promote host nutrition. This narrative review explores the theoretical potential of the functional components present in fermented foods to alter gut physiology and to impact the biological mechanisms thought to underpin depression and anxiety. Pre-clinical studies indicate the benefits of fermented foods in relieving perturbed gut function and for animal models of depression and anxiety. However, in humans, the literature relating to the relevance of fermented food for treating or preventing depression and anxiety is sparse, heterogeneous and has significant limitations. This review identifies a critical research gap for further evaluation of fermented foods in the management of depression anxiety in humans.