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Zinc and Depression: From Neurobiological Functions to Gut-Brain Interactions.
The global prevalence of depression and its profound burden on public health create an urgent need to explore novel interventions beyond conventional therapeutic strategies. Zinc, a key regulator in the central nervous system, exerts multiple biological functions beyond maintaining neurotransmitter homeostasis, including inhibiting neuroinflammation, restoring neuroplasticity, and modulating gut microenvironmental homeostasis. This review summarizes the evidence linking zinc deficiency to the onset and development of depression, with a specific focus on the role of gut microbiota. It also discusses different forms of zinc supplements, highlighting synergistic interventions that combine novel zinc complexes with probiotics. Together, these lines of evidence provide a theoretical basis for innovative adjunctive strategies for depression.
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Multi-omics analysis reveals Angelica sinensis-Carthamus tinctorius herb pair ameliorates diabetic retinopathy comorbid with depressive symptoms via the gut-eye-brain axis.
BACKGROUND: Diabetic retinopathy (DR) comorbid with depressive symptoms represents a significant public health challenge. The limitations of monotherapeutic approaches and the complex interplay between DR and depression highlight the need for comprehensive, integrated treatment strategies. PURPOSE: This study aimed to explore the therapeutic efficacy and underlying mechanisms of the Angelica sinensis-Carthamus tinctorius herb pair (ACHP) in addressing DR comorbid with depressive symptoms, utilizing an integrative multi-omics approach. METHODS: The chemical composition of ACHP was characterized using UPLC-MS. A DR mouse model exhibiting depressive-like behaviors was established through streptozotocin induction and long-term social isolation. The therapeutic effects and mechanisms of ACHP were evaluated using immunofluorescence, qRT-PCR, ELISA, non-targeted metabolomics, and 16S rRNA sequencing. Correlation analysis was conducted to elucidate the relationships among gut and ocular microbiota, serum metabolites, and clinical indices related to DR and depressive symptoms. RESULTS: ACHP treatment significantly alleviated hyperglycemia, retinal thinning, and depressive-like behaviors in the model mice. Multi-omics analysis revealed that ACHP restored gut microbiota balance by increasing beneficial Lactobacillus and reducing pathogenic genera such as Dubosiella and Faecalibaculum, while also reshaping ocular microbiota by suppressing pro-inflammatory Achromobacter and Pseudomonas. ACHP enhanced intestinal barrier integrity through upregulation of occludin, ZO-1 and MUC-2 and attenuated systemic and neuroinflammatory responses by reducing levels of LPS, TNF-α, IL-6, and IL-1β. Metabolomic profiling revealed that ACHP normalized glycerophospholipid metabolism-crucial for reducing inflammation and oxidative stress-specifically by inhibiting PLA2 and COX-2 while upregulating PPARγ. Correlation network analysis further emphasized the interactions among gut/ocular microbiota, inflammatory markers, and metabolites, highlighting the central role of the gut-eye-brain axis. CONCLUSION: These findings demonstrate that ACHP alleviates DR-depression comorbidity by synergistically targeting microbial dysbiosis, metabolic dysregulation, and inflammatory cascades across the gut-eye-brain axis. This study provides a novel, holistic therapeutic strategy rooted in traditional Chinese medicine, offering new insights into treating complex comorbid conditions.
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Effect of probiotic supplement on improvement of depressive symptoms in patients with substance-induced depressive disorder: a randomized, double-blind, placebo-controlled clinical trial.
BACKGROUND: Substance-Induced Depressive Disorder (SIDD) accounts for a high health burden and requires new therapies. Bidirectional communications between the gut and the brain mediated by the microbiota point to a possible influence of probiotics as a tool for preserving mental health. MATERIALS AND METHODS: Double-blind, placebo-controlled, randomized clinical trial on a sample of 40 patients with SIDD. Patients were then randomly assigned into probiotic and placebo arms and underwent interventions for four continuous weeks. The clinical assessment was done using BDI and HAM-A. Immunologic outcomes were measured through analysis of inflammatory markers, cytokines, and other immunological parameters. The trial was registered with ClinicalTrials.gov, under the identifier NCT06790823 (18/1/2025). RESULTS: The change in the intensity of depression and anxiety in both probiotic and placebo groups was statistically significant after intervention. No differences were also noted between the two groups. Immunologic results showed a suggestive changes in IL6 and INFG levels in the probiotic group as compared with placebo, which may indicate possible immune-modulating effects. CONCLUSION: In this randomized, double‑blind, placebo‑controlled pilot trial, both probiotic and placebo groups showed significant improvements in depressive and anxiety symptoms over time, with no significant between‑group differences. Probiotic supplementation was associated with non‑significant trends in selected inflammatory markers, suggesting possible immunological effects that warrant further investigation. Larger, multicenter trials with comprehensive microbiome and immunologic assessments are needed to clarify the potential role of probiotics as an adjunctive strategy in substance‑induced depressive disorder.
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The role of gut microbiota and blood metabolites in postpartum depression: a Mendelian randomization analysis.
BACKGROUND: Postpartum depression (PPD) is a common complication of pregnancy that imposes a heavy health and economic burden on individuals, families and society. The etiology of PPD is complex and incompletely defined, and recent studies have identified an important role for gut microbiota (GM) and their metabolites in neurological disorders. However, fewer studies on GM and PPD are available and have not yielded uniform results. METHODS: Instrumental variables for GM and blood metabolites were obtained from the MiBioGen consortium and metabolomics GWAS server. Single nucleotide polymorphisms (SNPs) associated with PPD phenotypes were obtained from the FinnGen consortium. Inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods were used to assess causal effects. Inverse MR analysis and sensitivity analysis were also utilized to improve the stability of the results. RESULTS: In this study, 5 intestinal species and 24 blood metabolites causally associated with PPD were identified using MR analysis. In addition, MR analysis showed that Prevotellaceae and Bifidobacteria may reduce the risk of PPD by elevating Xanthine and 1-arachidonoylglycerophosphoinositol (LysoPI) levels. CONCLUSIONS: This study identified GM and blood metabolites causally associated with PPD. The results of this study may provide a theoretical basis for the discovery of PPD-related biomarkers and the treatment of the disease by regulating the gut microenvironment.
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WenDan Decoction activates neuronal autophagy in the hippocampus via the gut-brain axis to improve depressive-like behavior in HFD mice.
BACKGROUND: High-fat diet (HFD) is implicated in depression pathogenesis. WenDan Decoction (WDD), a classical traditional Chinese medicine formula, shows promise for metabolic and psychiatric disorders, but its precise mechanisms require elucidation. METHODS: The chemical constituents of WDD were characterized by UPLC-MS/MS. The antidepressant effects of WDD in HFD mice were evaluated through behavioral tests, ELISA, and histopathology. Gut-brain axis mechanisms were investigated via 16S rRNA sequencing, untargeted metabolomics, network pharmacology, Nissl staining, transmission electron microscopy, Western blot, and RT-qPCR. Validation was performed through antibiotic depletion, fecal microbiota transplantation (FMT), and exogenous prostaglandin F2α (PGF2α) supplementation experiments. RESULTS: WDD administration significantly ameliorated depressive-like behaviors of HFD mice with relatively low hepatorenal toxicity. It restored intestinal mucosal integrity, mitigated inflammation, re-established gut microbial homeostasis and subsequently regulated arachidonic acid metabolism. Correlation analysis revealed that the strongest negative association between the differential microbiota Lactobacillus murinus and the arachidonic acid metabolite PGF2α. WDD attenuated blood-brain barrier disruption by diminishing pro-inflammatory metabolites, suppressed PI3K/AKT/mTOR pathway, and restored autophagic flux, thereby rescuing neuronal ultrastructural and functional impairments. The application of PI3K agonists reversed the effective regulation of WDD. Crucially, FMT experiments further confirmed that the gut microbiota and metabolite PGF2α are essential for WDD's antidepressant effects. CONCLUSION: WDD ameliorates depressive-like behaviors in HFD mice by modulating the gut microbiota and metabolism to suppress PI3K/AKT/mTOR pathway activation and restore autophagic flux. This study provides crucial mechanistic insights into WDD's effects against depression.
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Low-Molecular-Weight Peptides from Musca domestica Larvae Alleviate Diarrhea-Predominant Irritable Bowel Syndrome Comorbid with Depression via Regulating Gut Microbiota, Short-Chain Fatty Acids and Serum Metabolism.
Diarrhea-predominant irritable bowel syndrome (IBS-D) frequently occurs alongside depression, greatly impairing patients' life quality, with limited targeted treatments. Low-molecular-weight peptides (LMWPs) from Musca domestica larvae exert gut-protective bioactivities, but their efficacy and molecular mechanisms for comorbid IBS-D and depression remain unelucidated. A chronic-acute combined stress (CACS)-induced rat model of IBS-D complicated with depression was established and treated with LMWPs. The study evaluated intestinal and depressive behavioral phenotypes, and integrated 16S rRNA sequencing, untargeted serum metabolomics and quantitative detection of fecal SCFAs for multi-omics correlation analysis. 1. CACS triggered typical comorbid symptoms, which LMWPs alleviated with effects similar to trimebutine maleate. 2. LMWP treatment was associated with reshaped gut microbiota, restored metabolic pathways, altered levels of 27 disease-associated serum metabolites, and increased fecal SCFA levels. 3. Multi-omics correlation analyses suggested that the therapeutic benefits may involve crosstalk among gut microbiota, SCFAs, and tryptophan metabolites. Larva-derived LMWP relieves IBS-D combined with depression by modulating gut microecology, SCFA generation and serum metabolic balance through the gut-brain axis, which can serve as a novel promising therapeutic candidate.
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Comorbid depression exacerbates Gelsemium elegans toxicity via disruption of the Clostridium-LCA-PXR-CYP3A11 metabolic axis.
Gelsemium elegans (G. elegans) is a toxic medicinal plant traditionally used to treat chronic pain, with its toxicity linked to indole alkaloids such as gelsemine and humantenmine (HMT). Chronic pain often co-occurs with depression, a condition known to disrupt host-microbiota interactions, potentially affecting drug metabolism and toxicity. However, the impact of comorbid depression on the toxicity of G. elegans remains unclear. This study investigates how depression exacerbates the neurotoxicity of G. elegans and explores the role of the gut microbiota-host metabolic axis in this process. Depression-model mice were treated with G. elegans aqueous extract, gelsemine and HMT. Multi-omics approaches, including 16S rRNA sequencing and shotgun metagenomics, were used to analyze microbiota changes under depressive conditions. Functional validation was performed using pseudo-germ-free mice, fecal microbiota transplantation, and supplementation with Clostridium species and lithocholic acid (LCA), as well as pregnane X receptor (Pxr) knockout models. The results showed that depression significantly heightened the neurotoxicity of G. elegans, gelsemine and HMT. Mechanistically, depression reduced Clostridium abundance and LCA levels, impairing PXR activation and downregulating hepatic CYP3A11 expression. This disruption of the Clostridium-LCA-PXR-CYP3A11 axis hindered the detoxification of indole alkaloids, leading to increased systemic exposure and exacerbated neurotoxicity. Restoration of this pathway through Clostridium or LCA supplementation alleviated the toxicity. These findings highlight the role of the Clostridium-LCA-PXR-CYP3A11 axis in the altered toxicity of G. elegans in a depressive state, and suggest that Clostridium species and their metabolites may serve as a potential strategy for mitigating toxicity.
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Intestinal microbiota - a key to understanding the pathophysiology of anorexia nervosa?
Anorexia nervosa (AN) is a psychiatric disorder related to very serious consequences for physical and mental health of patients. Due to a complex clinical picture, which consists of anumber of somatic and mental symptoms, AN remains a serious problem of modern medicine and encourages the search for possible causes of the illness and new, more effective therapies. The recent reports emphasize the role of the intestinal microbiota in regulation of body weight. In this light, the hypothesis that in AN patients there is a significant imbalance of the intestinal microbiota, which contributes to the pathogenesis of the illness, seems interesting. The results of the latest research suggest that abnormal composition of the intestinal microbiota may be an important factor supporting cachexia of AN patients. Detailed analyzes of the composition of the microbiota characteristic for anorexia nervosa could be useful in developing new methods for monitoring and treatment of this illness. This paper aims to present the current state of the art about the role of the intestinal microbiota in the pathogenesis, course and treatment of AN.
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Marital distress, depression, and a leaky gut: Translocation of bacterial endotoxin as a pathway to inflammation.
BACKGROUND: Marital distress and depression work in tandem to escalate risks for inflammation-related disorders. Translocation of bacterial endotoxin (lipopolysaccharide, LPS) from the gut microbiota to blood circulation stimulates systemic inflammatory responses. METHODS: To investigate increased gut permeability (a "leaky gut") as one potential mechanistic pathway from marital distress and depression to heightened inflammation, this secondary analysis of a double-blind, randomized crossover study examined serial assessments of two endotoxin biomarkers, LPS-binding protein (LBP) and soluble CD14 (sCD14), as well as C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) during two separate 9.5 h visits. The 43 (N = 86) healthy married couples, ages 24-61 (mean = 38.22), discussed a marital disagreement during both visits; behavioral coding of these interactions provided data on hostile marital behaviors, a hallmark of marital distress. The Structured Diagnostic Interview for DSM-IV assessed participants' mood disorder history. RESULTS: Participants with more hostile marital interactions had higher LBP than those who were less hostile. Additionally, the combination of more hostile marital interactions with a mood disorder history was associated with higher LBP/sCD14 ratios. Higher LBP and LBP/sCD14 were associated with greater CRP production; for example, only 21% of low LBP participants (lowest quartile) had average CRP across the day > 3, compared to 79% of those in the highest quartile. Higher sCD14 was associated with higher IL-6. CONCLUSIONS: These bacterial LPS translocation data illustrate how a distressed marriage and a mood disorder history can promote a proinflammatory milieu through increased gut permeability, thus fueling inflammation-related disorders.
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Psychobiotics: A new approach for treating mental illness?
Gut microbiomes may have a significant impact on mood and cognition, which is leading experts towards a new frontier in neuroscience. Studies have shown that increase in the amount of good bacteria in the gut can curb inflammation and cortisol level, reduces symptoms of depression and anxiety, lowers stress reactivity, improves memory and even lessens neuroticism and social anxiety. This shows that, probably the beneficial gut bacteria or probiotics function mechanistically as delivery vehicles for neuroactive compounds. Thus, a psychobiotic is a live organism, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness. Study of these novel class of probiotics may open up the possibility of rearrangement of intestinal microbiota for effective management of various psychiatric disorders.