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Effect and mechanism of maternal prolactin levels on depressive-like behavior in prenatally stressed offspring.
Prenatal stress (PS) has an adverse impact on the neurodevelopment of the fetus and increases the risk of depression in offspring. Prolactin (PRL), a polypeptide hormone released by the pituitary gland, has a promising neuroprotective effect. However, it is not clear whether the decline in PRL levels during gestation is related to the depressive-like behavior of offspring caused by PS. This study aimed to assess the role and mechanism of PRL during gestation on depressive-like behavior in PS offspring rats. We found that PS led to a marked decrease in serum PRL levels of the maternal rats, accompanied by depressive-like behavior in offspring rats. Exogenous PRL supplementation during pregnancy significantly mitigated depressive-like behavior, ameliorated neuronal damage and neuroinflammation, and restored synaptic plasticity in the medial prefrontal cortex (mPFC) of PS offspring rats. Further investigation confirmed that PRL exerted a neuroprotective effect by activating the cAMP signaling in the mPFC of PS offspring rats. Single cell RNA (scRNA) sequencing revealed that PRL administration during pregnancy resulted in the alterations of immune cell proportions, such as microglia, granulocytes, and B cells. Further analysis of microglia found that the differentially expressed genes (DEGs) in microglia were involved in multiple immune-related signaling pathways. Meanwhile, PRL intervention switched microglial polarization toward the M2 phenotype in PS offspring rats. Additionally, PRL administration during pregnancy effectively ameliorated gut microbiota disturbances in PS offspring rats. Our findings proposed that PRL administration during pregnancy could significantly mitigate depressive-like behavior in PS offspring rats by modulating cAMP signaling-mediated synaptic plasticity, facilitating microglial M2 polarization, and ameliorating gut microbiota dysbiosis.
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The microbiota-gut-brain axis in depression: unraveling the relationships and therapeutic opportunities.
Depression, a highly prevalent and relapsing mental disorder, exacts profound personal and socioeconomic tolls globally, warranting urgent scientific and clinical attention. Emerging evidence from both preclinical models and human clinical investigations has established the microbiota-gut-brain axis (MGBA) as a critical determinant in depression pathogenesis. This intricate bidirectional network integrates gut microbiota with central nervous system function, influencing mental health through mechanisms previously underrecognized. This review systematically synthesizes gut microbiota alterations associated with depression and their impacts on neuroendocrine, neuroimmune, and metabolic pathways. Advanced therapeutic strategies targeting the MGBA are discussed, including probiotics, fecal microbiota transplantation, and artificial intelligence-enabled microbiome interventions for depression management. While challenges in standardization, mechanistic understanding, efficacy and safety remain, MGBA-centered approaches offer a promising shift toward microbiota-based diagnostics and personalized treatments for depression.
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Meta-analysis of the association between gut microbiota and postpartum depression.
OBJECTIVE: This study aimed to explore the association between gut microbiota and postpartum depression (PPD) through meta-analysis, providing a basis for effective clinical preventive interventions.. METHODS: Systematic searches were conducted in English databases (Cochrane Library, Embase, Web of Science, PubMed) for studies published up to April 2025. Literature screening used a double-blind method, and quality assessment was performed with the AHRQ methodological tool evaluating 11 core dimensions. Meta-analysis was conducted using STATA 18.0 software on eligible studies. RESULTS: Twelve studies were included. α-Proteobacteria was a significant risk factor for PPD (OR = 1.19, 95%CI: 1.11-1.28, p < 0.05). Protective factors included Bifidobacterium (OR = 0.82), Ruminococcaceae (OR = 0.88), Prevotellaceae (OR = 0.89), Veillonellaceae (OR = 0.83), and Clostridia (OR = 0.84). Included studies showed low heterogeneity, with robust results and low publication bias risk. CONCLUSION: PPD is closely linked to specific gut microbiota imbalances. α-Proteobacteria may increase PPD risk via inflammatory responses, while beneficial microbiota exert protective effects through neurotransmitter regulation, short-chain fatty acid metabolism, and gut-brain axis modulation. Gut microbiota could serve as a target for PPD intervention and prevention.
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Fndc5/irisin deficiency leads to dysbiosis of gut microbiota contributing to the depressive-like behaviors in mice.
BACKGROUND: Depression is one of the most common mental diseases and the leading cause of disability worldwide. A dysfunctional gut microbiota-brain axis is one of the main pathological bases of depression. Irisin, an exercise-related myokine, reduces depression-like behaviors and may guide the relief of depressive symptoms by exercise. However, its underlying mechanism remains unclear. METHODS: Fibronectin type III domain containing 5 (Fndc5)/Irisin was knocked out in male wide-type C57BL/6N mice using CRISPR-cas9. The depression and anxiety symptoms were examined in irisin knockout and control mice with or without chronic unpredictable mild stress by sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Fecal microbiota was assessed by 16S rRNA sequencing and microbiota-related metabolites using liquid chromatography with tandem mass spectrometry. Differential metabolites were analyzed with the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: The knockout mice showed anxiety- and depression-like behaviors and altered diversity and richness of gut microbiota. At the phylum level, these mice had decreased Firmicutes and increased Bacteroidota populations, while at the genus level, they exhibited a low relative abundance of Lactobacillus and Bifidobacterium. Moreover, knocking out of Irisin gene in these mice significantly reduced N-desmethyl-mifepristone (RU 42633) and elevated (-)-stercobilin levels. The KEGG results showed that the microbiota-related metabolites affected by irisin mainly clustered into arginine and proline metabolism and affected the mechanistic target of rapamycin kinase (mTOR) signaling pathway. CONCLUSION: Our findings show that Fndc5/irisin deficiency causes depression in mice by inducing dysbiosis of gut microbiota and changes in microbiota-related metabolites.
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Exploring the associations between gut microbiota and male depression: an integrated study of mendelian randomization and animal experiment.
BACKGROUND: Depression is a major global health concern. Although multiple observational and Mendelian randomization (MR) studies have suggested an association between gut microbiota (GM) and depression, the causal relationship between specific GM taxa and male depression remains unclear. METHODS: We conducted MR analysis to investigate the causal relationship between GM and male depression. The primary analysis employed the inverse variance weighted method, and additional MR and sensitivity analyses were performed to ensure the robustness of the results. To provide supportive evidence for the MR results, we evaluated changes in relevant microbial taxa using 16S rDNA sequencing in male rats subjected to chronic unpredictable mild stress. Taxa that showed significant differences in both the MR analysis and the animal model were selected for correlation analysis with depression-related behavioral indicators. RESULTS: Through MR analysis, we identified potential positive causal relationships between Eubacterium oxidoreducens group, Anaerotruncus, Ruminiclostridium 9, and Streptococcus and male depression. Additional MR approaches and sensitivity analyses supported the robustness of these findings. Among the four taxa, only Ruminiclostridium 9 exhibited a significantly increased relative abundance in the depression model group compared to the control group. Correlation analysis further revealed that Ruminiclostridium 9 was negatively associated with sucrose preference test and total distance in the open field test, and positively associated with immobility time in the forced swim test. CONCLUSION: Our study provides both genetic and biological evidence supporting Ruminiclostridium 9 as a potential risk factor for male depression, highlighting its potential as a therapeutic target and prognostic biomarker for evaluating treatment efficacy. These findings offer novel insights into the diagnosis and management of male depression.
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Exploring the hypothetical role of Bacteroides species in depression progression: insights from metagenomic analysis.
Depression, a psychiatric disorder with significant morbidity and mortality, has a complex etiology. Recent advances in microbiome research have highlighted the potential role of fecal microbiota in depression pathogenesis. This study utilized shotgun metagenomic sequencing to compare the fecal microbiota of 28 depression patients and 26 healthy individuals. Significant differences in fecal microbiota composition were observed between the two groups. We generated 350 non-redundant high-quality metagenome-assembled genomes (MAGs) by binning and conducted comparisons between the depression and control groups. Notably, we found that the MAGs enriched in people with depression mostly belonged to Bacteroides, indicating a close link between Bacteroides abundance and the development of depression, suggesting that Bacteroides might be a potential culprit for depression. In the depression group, we found that the module of nitric oxide synthesis was remarkably enriched, and all Bacteroides MAGs contained genes annotated as nitric oxide synthase, suggesting that increased levels of Bacteroides may contribute to elevated nitric oxide synthesis. A distinct microbial signature consisting of Arthrobacter sp._U41, Bacillus cereus, Campylobacter rectus, and Pasteurella dagmatis accurately discriminates between depressed individuals and healthy controls, achieving an average area under the receiver operating characteristic curve of 0.950. This research sheds light on the potential role of fecal microbiota in depression and highlights specific metabolic pathways and microbial markers for further investigation.IMPORTANCEThis research highlighted significant differences in the composition and function of fecal microbiota between individuals with depression and healthy individuals, particularly the enrichment of Bacteroides metagenome-assembled genomes (MAGs) in depression patients. The upregulation of the nitric oxide synthesis pathway associated with these MAGs belonging to Bacteroides in the gut of depression patients had also been observed. The selected bacterial biomarkers reliably differentiate depression cases from healthy controls with high diagnostic accuracy (mean area under the receiver operating characteristic curve = 0.950). Our results suggest the importance of exploring microbial markers as potential diagnostic and therapeutic targets in managing depression.
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Metabolomic and inflammatory signatures of symptom dimensions in major depression.
BACKGROUND: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. METHODS: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. RESULTS: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. CONCLUSION: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.
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Identification of characteristic microbes and metabolites in confined environments population.
Chronic stress in confined environments can disrupt the microbiota-gut-brain axis. However, the characteristic microbial and metabolic alterations in socially and radically basic activity-restricted people in confined environments (SRBARC) remain unclear. This study integrated assessments of emotional states, gut microbiota, and metabolomic profiles to investigate theirinterrelationships in SRBARC, aiming to identify characteristic microbes and metabolites. The results suggested that the SRBARC tend to exhibit depressive/anxiety-like behaviors, accompanied by hypothalamic-pituitary-adrenal (HPA) axis activation, suppressed testosterone, and elevated pro-inflammatory cytokines. Full-length 16S rDNA sequencing analysis indicated lower Shannon and Chao1 indices in the gut microbiota of the SRBARC. Random forest analysis combined with dual-cohort verification suggested that Blautia massiliensis, Blautia wexlerae, Coprococcus comes, Faecalibacterium prausnitzii, and Lachnospiraceae bacterium may serve as characteristic microbes with diagnostic value (discovery cohort AUC = 0.836, validation cohort AUC = 0.840). Metabolomic analysis of feces, serum and urine revealed alterations in amino acid metabolism and disruptions in tetrahydrobiopterin (BH4) synthesis in the SRBARC, which affected serotonin (5-HT) and dopamine (DA) pathways. Four metabolites, including 5-methoxytryptophol, were identified as potentially metabolites associated with emotional states. These characteristic microorganisms and metabolic features were associated with neuroinflammation and immunity, and their interactions may play a key role in regulating emotional states in SRBARC. In summary, this study suggested a potential interplay among gut microbiota, neurotransmitter metabolism, and emotional states in the SRBARC, identifying potential key microbial signatures and metabolites that may provide a theoretical foundation for developing gut microbiota-based intervention strategies.
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Quinoa Saponin Ameliorates Lipopolysaccharide-Induced Behavioral Disorders in Mice by Inhibiting Neuroinflammation, Modulating Gut Microbiota, and Counterbalancing Intestinal Inflammation.
Triterpenoids derived from plants are a promising class of natural antidepressants. This research focused on the therapeutic potential of quinoa saponin (QS) in alleviating lipopolysaccharide (LPS)-induced anxiety and depressive-like behaviors in mice. The most abundant saponin fraction, QS-3, was isolated from QS extracts, and its major saponin components and chemical structure were elucidated. Six pentacyclic triterpene saponins and three tetracyclic triterpene saponins were identified in QS-3, with phytolaccagenin and oleanolic acid being the dominant sapogenins. In vivo studies demonstrated that QS significantly mitigated LPS-induced anxiety and depressive-like behaviors in mice, enhanced the levels of neurotrophic proteins, key synaptic proteins, and neurotransmitters, and restored synaptic function and neuronal damage. Furthermore, QS inhibited neuroinflammation by curtailing the activity of the TLR4/MyD88/NF-κB pathway and modulating microglial phenotypes. Notably, QS also ameliorated colonic inflammation by promoting gut microbiota homeostasis and increasing short-chain fatty acids (SCFAs) production, which contributed to the improvement of anxiety and depressive behaviors in mice. Our findings suggest that QS holds potential as a natural dietary supplement for the treatment and prevention of anxiety and depression, possibly through its modulation of gut-brain axis dynamics and suppression of the activation of the TLR4/MyD88/NF-κB pathway.
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The neuroactive potential of the human gut microbiota in quality of life and depression.
The relationship between gut microbial metabolism and mental health is one of the most intriguing and controversial topics in microbiome research. Bidirectional microbiota-gut-brain communication has mostly been explored in animal models, with human research lagging behind. Large-scale metagenomics studies could facilitate the translational process, but their interpretation is hampered by a lack of dedicated reference databases and tools to study the microbial neuroactive potential. Surveying a large microbiome population cohort (Flemish Gut Flora Project, n = 1,054) with validation in independent data sets (ntotal = 1,070), we studied how microbiome features correlate with host quality of life and depression. Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators. Together with Dialister, Coprococcus spp. were also depleted in depression, even after correcting for the confounding effects of antidepressants. Using a module-based analytical framework, we assembled a catalogue of neuroactive potential of sequenced gut prokaryotes. Gut-brain module analysis of faecal metagenomes identified the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid as correlating positively with mental quality of life and indicated a potential role of microbial γ-aminobutyric acid production in depression. Our results provide population-scale evidence for microbiome links to mental health, while emphasizing confounder importance.