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Alterations in fecal microbiota composition and cytokine expression profiles in adolescents with depression: a case-control study.
Emerging evidence has highlighted that altered gut microbiota are associated with the onset and progression of depression via regulating the gut-brain axis. However, existing research has predominantly focused on children and adults, frequently neglecting adolescent depression. Given the rising prevalence and substantial impact of adolescent depression on functional impairment and suicidality, it is essential to focus more on this age group. In this study, we examined the fecal microbiota and inflammatory profiles of 99 depressed adolescents and 106 age-matched healthy controls using Illumina NovaSeq sequencing and multiplex immunoassays, respectively. Our findings revealed lower bacterial α-diversity and richness, alongside altered β-diversity in adolescents with depression. Gut dysbiosis associated with adolescent depression was characterized by increased pro-inflammatory genera such as Streptococcus and decreased anti-inflammatory genera like Faecalibacterium. These differential genera may serve as potential non-invasive biomarkers for adolescent depression, either individually or in combination. We also observed disruptions in the inferred microbiota functions in adolescent depression-associated microbiota, particularly in glycolysis and gluconeogenesis. Additionally, depressed adolescents exhibited systemic immune dysfunction, with elevated levels of pro-inflammatory cytokines and chemokines, which showed significant correlations with the differential genera. Our study bridges the gap between children and adults by providing new insights into the fecal microbiota characteristics and their links to immune system disruptions in depressed adolescents, which offer new targets for the diagnosis and treatment of depression in this age group.
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Blood metabolites mediate gut microbiota effects on depression: A Mendelian randomization study.
BACKGROUND: Accumulating evidence indicates that gut microbiota (GM) influence depression via gut-brain axis signaling, yet the causal relationships and underlying mechanisms are not fully understood. We conducted bidirectional Mendelian randomization (MR) to assess GM-Depression causal effects, with additional analyses examining blood metabolite mediation. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using genetic instruments for gut microbiota (GM) from the FINRISK 2002 cohort (n = 5959). Depression data were obtained from the FinnGen R11 database (n = 448,069, European ancestry), along with three additional independent datasets: Pan-UK Biobank (n = 370,457), Jamapsy_Giannakopoulou (n = 194,548), and PGC-noUKBB (n = 688,808). A Mendelian randomization meta-analysis was performed combining these datasets. Mediation analysis was conducted using multivariable MR (MVMR) with blood metabolite data from the Canadian Longitudinal Study on Aging (CLSA, n = 8299). Pathway analysis was performed using MetaboAnalyst 5.0. RESULTS: Our bidirectional MR identified Bifidobacteriaceae as a protective factor against depression (IVW OR = 0.93, 95 % CI: 0.89-0.97, P < 0.001), confirmed by meta-analysis (β = -0.05, P = 0.002). The protection was mediated by metabolites (e.g., glycolithocholate sulfate; OR = 0.80, 95 % CI: 0.71-0.90) enriched in BCAA pathways (FDR = 0.013). Conversely, Negativibacillus sp000435195 showed nominal risk effects in IVW (OR = 1.09, 95 % CI: 1.04-1.15, P < 0.001), though meta-analysis did not support this (P > 0.05; I2 = 68.5 %). Its potential risk involved metabolites (e.g., sulfated piperine; OR = 1.27, 95 %CI:1.13-1.42) enriched in glycine/serine/threonine pathways (FDR = 0.002). Reverse MR excluded reverse causation (all P > 0.05). CONCLUSIONS: Our findings provide genetic evidence for the causal involvement of specific GM in Depression, mediated by distinct metabolic pathways, suggesting potential microbiota-based interventions for Depression treatment.
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The microbiota-gut-brain axis in pathogenesis of depression: A narrative review.
The microbiota-gut-brain axis is a bidirectional regulatory pathway between the brain and the gastrointestinal tract, which plays an important role in maintain homeostasis. Gut microbiota could influence the behavior, cognition, stress response and others via the axis. Depression is a complex psychiatric disease, giving rise to heavy social health and economic burden. In recent years, studies have shown that the gut microbiota are closely linked to the pathophysiological processes of depression. In this article, the interaction and its underlying mechanisms between depression and gut microbiota were summarized.
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Differential gut microbiota and microbial metabolites in adolescents with depression.
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A Mechanism-Guided Delivery System for Long-Acting Postpartum Depression Therapy via Hydrogen-Facilitated Gut Microbiota Reprogramming.
To address the limitations of current pharmacotherapies for postpartum depression (PPD), this study developed an innovative oral delivery system (EL@HRG) based on calcium-cross-linked alginate/WPI emulsion nanogel particles, leveraging the mechanism reported in Cell where in hydrogen (H2) drives the gut commensal bacterium Eggerthella lenta to convert host corticosterone into the neuroactive steroid allopregnanolone. The core innovation of this work lies in the of a controlled hydrogen-release carrier with a probiotic delivery platform into a unified system. Using a scaffold of sodium alginate and whey protein integrated with corn oil to form an emulsion, we leveraged the higher solubility of H2 in the oil phase to overcome the key bottleneck of maintaining effective intestinal hydrogen concentration after oral administration. Concurrently, l-arginine, an essential nutrient for E. lenta growth, was incorporated into the gel network, achieving an integrated "delivery-colonization-activation" function. In vitro experiments confirmed that EL@HRG provided sustained hydrogen release and efficiently encapsulated viable bacteria. In vivo studies demonstrated that EL@HRG significantly enhanced the intestinal colonization and retention of E. lenta, leading to sustained activation of the steroid conversion pathway and elevated levels of allopregnanolone in the brain. In a PPD mouse model, EL@HRG, acting via the gut-brain axis, inhibited hippocampal neuroinflammation, restored synaptic plasticity and GABAergic signaling, and consequently markedly improved depressive-like behaviors, anxiety, and maternal behavior deficits. Its therapeutic efficacy showed enhanced sustainability compared to the short-term effects of injected allopregnanolone, with no observed systemic toxicity. Metabolomic analysis further revealed a reshaping of the "steroid hormone biosynthesis" pathway, underpinning the therapeutic effect. In conclusion, this study provides a novel, nonpharmacological, long-acting, and safe interventional strategy for PPD. It also establishes a new paradigm of mechanism-guided delivery systems for precisely modulating the gut microenvironment to achieve specific physiological functions.
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The Impact of Gut Microbiota on the Development of Anxiety Symptoms-A Narrative Review.
The gut microbiota plays a key role in mental health, with growing evidence linking its composition to anxiety and depressive disorders. Research on this topic has expanded significantly in recent years. This review explores alterations in the gut microbiota of individuals with anxiety disorders and examines the potential therapeutic effects of probiotics. Background/Objectives: This review aims to analyze the alterations in gut microbiota composition in individuals with anxiety disorders and evaluate the potential therapeutic effects of probiotics in mitigating symptoms. By examining recent research, this study seeks to highlight the gut-brain connection and its implications for mental health interventions. Materials and Methods: A literature search was conducted in PubMed, Embase, CINAHL, and Google Scholar, focusing on studies investigating the relationship between gut microbiota and anxiety disorders, as well as the impact of probiotics on symptom severity. Results: The reviewed studies suggest that individuals with anxiety disorders often exhibit gut microbiota alterations, including reduced microbial diversity and a lower abundance of short-chain fatty acid-producing bacteria. Additionally, probiotics, particularly those from the Lactobacillus genus, may help alleviate anxiety symptoms by modulating gut microbiota composition. Conclusions: Gut dysbiosis appears to be closely linked to anxiety disorders, and probiotic interventions could represent a promising therapeutic avenue. However, further research is needed to clarify underlying mechanisms and optimize treatment strategies.
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Ginsenoside Rh1 inhibits tumor growth in mice with colorectal cancer and depressive symptoms via modulation of the gut microbiota and tumor microenvironment.
Depression can accelerate the progression of colorectal cancer (CRC), and depressive remission improves cancer outcomes. Ginsenoside Rh1, the main metabolite of a steroidal saponin extracted from Panax ginseng, improves memory and learning and to inhibit tumor growth. However, its anticancer effects and mechanisms in CRC complicated by psychological stress remain unclear. The present study aimed to investigate the protective effect of Rh1 against CRC with coexisting symptoms of depression. A CRC xenograft mouse model exposed to chronic restraint stress (CRS) was established. Behavioral changes, 5‑hydroxytryptamine (5‑HT) levels, cytokine expression, intestinal microbiota diversity, T‑cell recruitment, myeloid‑derived suppressor cell (MDSC) proportions and dendritic cell (DC) maturation were analyzed following treatment of the mice with Rh1. Results showed that Rh1 inhibited tumor growth, ameliorated depressive‑like behaviors, enhanced cognitive function, upregulated brain 5‑HT and serum noradrenaline levels, and decreased serum cortisol, corticotropin‑releasing hormone, adrenaline, interleukin‑6, C‑X‑C motif chemokine ligand 1 and tumor necrosis factor‑α levels in mice with CRC under CRS. Furthermore, Rh1 intervention attenuated gut dysbiosis and decreased the Firmicutes/Bacteroidota ratio. Antibiotic‑induced depletion of gut bacteria further confirmed the involvement of gut microbiota in the anticancer and antidepressant effects of Rh1. Rh1 also promoted T cell activation and DC maturation, and reduced MDSC frequency, thereby reshaping the immune microenvironment. These findings indicate that Rh1 inhibited CRC tumor growth in the CRS‑exposed mice by stimulating the immune response and modulating the gut microbiota. Thus, it is suggested that Rh1 has potential as a novel therapeutic strategy for patients with CRC and depression.
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Postbiotics as a Therapeutic Tool in Depression: Exploring into Molecular Pathways and Neuroprotective Effects.
Depression, a debilitating mood disorder characterized by persistent sadness and anhedonia, affects millions worldwide, yet available therapies remain suboptimal and often cause undesirable side effects. Emerging evidence highlights the crucial role of gut microbiota in regulating mental health through the gut-brain axis, paving the way for novel therapeutic strategies. As per preclinical and clinical studies, there is a causal relationship between gut dysbiosis and depression via modulation of brain activity through the gut-brain axis (GBA), and the key to targeting microbes is key to treating depression. Postbiotics-bioactive compounds derived after fermentation have been shown to provide several health benefits, particularly in terms of neuroinflammation, neurotransmitter imbalance, mitochondrial dysfunction, and restoration of neuroplasticity associated with depression. This review explores the neuroprotective mechanisms by which postbiotics alleviate depression, including the modulation of neurotransmitter synthesis, suppression of neuroinflammation, mitigation of oxidative stress and mitochondrial dysfunction, and restoration of neuroplasticity. Furthermore, postbiotics hold potential as adjuvant therapy alongside conventional antidepressants, enhancing treatment efficacy and minimizing side effects. Despite promising initial findings, challenges such as standardized formulation, clinical dose optimization, and regulatory framework development must be addressed. Large-scale clinical trials are imperative to validate their therapeutic potential and facilitate integration into mainstream depression management. As research advances, postbiotics may redefine mental health treatment, emerging as a revolutionary microbiome-based approach for long-term patient care.
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The Role of the Gut Microbiota in Dietary Interventions for Depression and Anxiety.
There is emerging evidence that an unhealthy dietary pattern may increase the risk of developing depression or anxiety, whereas a healthy dietary pattern may decrease it. This nascent research suggests that dietary interventions could help prevent, or be an alternative or adjunct therapy for, depression and anxiety. The relation, however, is complex, affected by many confounding variables, and is also likely to be bidirectional, with dietary choices being affected by stress and depression. This complexity is reflected in the data, with sometimes conflicting results among studies. As the research evolves, all characteristics of the relation need to be considered to ensure that we obtain a full understanding, which can potentially be translated into clinical practice. A parallel and fast-growing body of research shows that the gut microbiota is linked with the brain in a bidirectional relation, commonly termed the microbiome-gut-brain axis. Preclinical evidence suggests that this axis plays a key role in the regulation of brain function and behavior. In this review we discuss possible reasons for the conflicting results in diet-mood research, and present examples of areas of the diet-mood relation in which the gut microbiota is likely to be involved, potentially explaining some of the conflicting results from diet and depression studies. We argue that because diet is one of the most significant factors that affects human gut microbiota structure and function, nutritional intervention studies need to consider the gut microbiota as an essential piece of the puzzle.
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Study on the antidepressive effects and mechanism of raw and fried Ziziphi Spinosae Semen via metabolomics and gut microbiota analysis.
Ziziphi Spinosae Semen (ZSS) and fried ZSS (FZSS) have been used for treating insomnia and depression in China. However, the potential influence of chemical variations on their efficacy remains unclear. This study demonstrated that compared with ZSS, FZSS exhibited an increase in the content of seven compounds, while the fatty oil content decreased. Both ZSS and FZSS exhibited antidepressive effects in a chronic unpredictable mild stress rat model, indicating a synergistic regulation of deficiencies in 5-hydroxytryptamine in the brain and the hyperactivation of severe peripheral inflammation. ZSS demonstrated a superior modulatory effect compared with FZSS, as indicated by integrated pharmacodynamic index, metabolic profile, and relative distance value. The potential mechanism underlying their antidepressive effects involved the modulation of gut microbiota structure to alleviate excessive inflammatory responses and imbalanced tryptophan metabolism. Correlation analysis indicated that the higher fatty oil contents should be comprehensively considered as the main reason for ZSS's superior antidepressive effects, achieved through the regulation of pyroglutamic acid levels.