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An immunometabolic signature of major depressive disorder in systemic lupus erythematosus.
OBJECTIVES: Systemic lupus erythematosus (SLE) frequently affects the central nervous system, leading to neuropsychiatric SLE (NPSLE). Major depressive disorder in SLE (SLEMDD) is the most frequent manifestation of NPSLE and is believed to arise from an immune-mediated process. However, biomarkers for SLEMDD remain lacking. The aim of this study was to identify candidate immunometabolic biomarkers associated with SLEMDD. METHODS: We analysed deep flow cytometry immune phenotyping, gut microbiota profiling, and targeted mass spectrometry-based metabolomics from 99 patients from the LUPIL-2 study (NCT02955615). Biological signatures were identified using unsupervised principal component analysis and supervised decision tree classification. They were then validated in an independent cohort from the TRANSIMMUNOM study (NCT02466217). RESULTS: SLEMDD patients exhibited a distinct immune profile with decreased naïve CD4⁺ T cells and naïve regulatory T cells (Tregs), alongside increased ICOS⁺ effector memory Tregs (94% classification accuracy). Gut microbiota diversity was reduced with depletion of Akkermansia muciniphila and enrichment of Faecalibacterium prausnitzii. Metabolomic analyses revealed disruptions in kynurenine and short-chain fatty acid pathways, including decreased butyrate levels. Integrative analyses demonstrated coordinated alterations linking Treg activation, microbial metabolites, and immune pathways, distinguishing SLEMDD from SLEnon-MDD with up to 85% accuracy. CONCLUSIONS: SLEMDD is associated with an immunometabolic signature involving alterations in Treg phenotype, gut microbiota composition, and metabolic pathways. These findings provide a rationale for future immunoregulatory or microbiota-targeted therapeutic strategies in SLEMDD.
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Exploration of the Gut Microbiome in Thai Patients with Major Depressive Disorder Shows a Specific Bacterial Profile with Depletion of the Ruminococcus Genus as a Putative Biomarker.
Maes et al. (2008) published the first paper demonstrating that major depressive disorder (MDD) is accompanied by abnormalities in the microbiota-gut-brain axis, as evidenced by elevated serum IgM/IgA to lipopolysaccharides (LPS) of Gram-negative bacteria, such as Morganella morganii and Klebsiella Pneumoniae. The latter aberrations, which point to increased gut permeability (leaky gut), are linked to activated neuro-immune and oxidative pathways in MDD. To delineate the profile and composition of the gut microbiome in Thai patients with MDD, we examined fecal samples of 32 MDD patients and 37 controls using 16S rDNA sequencing, analyzed α- (Chao1 and Shannon indices) and β-diversity (Bray-Curtis dissimilarity), and conducted linear discriminant analysis (LDA) effect size (LEfSe) analysis. Neither α- nor β-diversity differed significantly between MDD and controls. Rhodospirillaceae, Hungatella, Clostridium bolteae, Hungatella hathewayi, and Clostridium propionicum were significantly enriched in MDD, while Gracillibacteraceae family, Lutispora, and Ruminococcus genus, Ruminococcus callidus, Desulfovibrio piger, Coprococcus comes, and Gemmiger were enriched in controls. Contradictory results have been reported for all these taxa, with the exception of Ruminococcus, which is depleted in six different MDD studies (one study showed increased abundance), many medical disorders that show comorbidities with MDD, and animal MDD models. Our results may suggest a specific profile of compositional gut dysbiosis in Thai MDD patients, with increases in some pathobionts and depletion of some beneficial microbiota. The results suggest that depletion of Ruminococcus may be a more universal biomarker of MDD that may contribute to increased enteral LPS load, LPS translocation, and gut-brain axis abnormalities.
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Lipid metabolic dysregulation-induced neuroinflammation in the pathophysiology of major depressive disorder.
Depressive disorders exhibit significant comorbidity with lipid dysregulation. Clinical observations indicate that poor lifestyle factors contribute to lipid dysregulation in depressed patients. This dysregulation disrupts gut microbiota homeostasis and endocrine balance. Mitochondria and endoplasmic reticulum, critical organelles for lipid metabolism, also show impaired homeostasis in depression, further contributing to lipid dysregulation. Such alterations activate peripheral and central immune-inflammatory responses, compromise blood-brain barrier integrity, and disrupt neuroimmune cytokine signaling. This process induces and aggravates neuroinflammation, thereby contributing to the onset and progression of depressive disorders. These disruptions in homeostasis further exacerbate lipid dysregulation. This review delineates the molecular mechanisms by which dysregulation of lipid metabolism exacerbates depressive disorders via neuroinflammatory pathways, offering critical insights into pathogenesis and therapeutic strategies.
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The protective effect of S-adenosylmethionine on chronic adolescent stress-induced depression-like behaviors by regulating gut microbiota.
The efficacy and tolerability of current antidepressants for adolescent depression are inadequate. S-adenosylmethionine (SAMe), known for its effectiveness and minimal side effects in adult depression, remains unstudied in adolescents. This study explored the potential of SAMe to address depression-like behaviors in juvenile rats induced by chronic unpredictable mild stress (CUMS), with a focus on gut microbiome interactions. Adolescent male Wistar rats were subjected to a 4-week CUMS regimen and received daily intraperitoneal injections of 300 mg/kg SAMe. Behavioral assessments included the sucrose preference test, elevated plus maze test, open field test, and Y-maze test. Histopathological changes of the hippocampus and colon were observed by Nissl staining and hematoxylin and eosin staining, respectively. Gut microbiome composition was analyzed using Accurate 16S absolute quantification sequencing. The results showed that SAMe significantly improved behavioral outcomes, reduced histopathological damages in hippocampal neurons and colon tissues, and modulated the gut microbiota of depressed rats. It favorably altered the ratio of Bacteroidetes to Firmicutes, decreased the absolute abundance of Deferribacteres, and adjusted levels of key microbial genera associated with depression-like behaviors. These results suggested that SAMe could effectively counter depression-like behaviors in CUMS-exposed adolescent rats by mitigating hippocampal neuronal and colon damage and modulating the gut microbiota. This supports SAMe as a viable and tolerable treatment option for adolescent depression, highlighting the importance of the gut-brain axis in therapeutic strategies.
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Limosilactobacillus reuteri-butyrate axis in depression therapy: A key pathway discovered through a novel preclinical human flora-associated animal model.
The transition from preclinical to clinical drug development is critically impeded by interspecies disparities, which limit the predictive validity of preclinical efficacy for human outcomes. To address this limitation, we established a human flora-associated depression rat (HFADR) model through fecal microbiota transplantation (FMT). The HFADR model bridges the preclinical-clinical translation by recapitulating conserved microbial-host interactions identified through multi-omics analysis in a chronic unpredictable mild stress (CUMS) rat model and in patients with major depressive disorder. The HFADR model simulated the pathophysiological characteristics of clinical depression validated by gut-brain axis indices, including microbial composition, inflammatory biomarkers, brain-derived neurotrophic factor (BDNF), and monoamine neurotransmitters. Employing geniposide, a bioactive iridoid compound derived from medicinal plants, as a therapeutic prototype, the HFADR model revealed the novel Limosilactobacillus reuteri-butyrate axis as a conserved regulatory hub for the treatment of depression. Geniposide administration restored L. reuteri abundance in the HFADR model, which significantly correlated with improved gut-brain axis homeostasis. Metabolomics confirmed that L. reuteri exerts antidepressant effects via butyrate restoration in CUMS mice, with parallel butyrate level alterations observed in geniposide-treated HFADR model. Both L. reuteri supplementation and exogenous butyrate administration reversed depression-like behavior, mechanistically confirming the axis by reduced hippocampal astrocyte activation and elevated Nrf2 expression. This study established the HFADR model as a translational tool for evaluating microbiota-targeted therapies and identified the L. reuteri-butyrate axis as a novel therapeutic target. Our findings provide a theoretical and practical framework for refining preclinical models and advancing antidepressant development using microbiome-based strategies.
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Impact of antidepressants on the composition of the gut microbiome: A systematic review and meta-analysis of in vivo studies.
BACKGROUND: There is a growing body of evidence suggesting that antidepressant drugs (ADs) alter the gut microbiome of persons with depressive disorders. Herein, we aim to investigate the gut microbial profile of AD-treated animal models of depression (MoD) and persons with major depressive disorder (MDD). METHODS: We conducted a systematic review and meta-analysis investigating the gut microbiome community-level diversity and relative abundance of microbial taxa in AD-treated animal MoD and persons with MDD. RESULTS: 24 human studies (898 participants) and 48 animal studies (849 subjects) were identified. Nonsignificant differences in gut microbial richness were observed between AD-treated and nonmedicated animals and humans. Beta diversity analysis in animals shows that AD intake is linked to a distinct gut microbial profile, a result not observed in humans. Consistent depletion of the genera Faecalibacterium and Parasutterella, along with enrichment of Bifidobacterium, was observed in AD-treated persons with MDD. In AD-treated animals, AD intake was associated with depletion of Flavobacterium and Adlercreutzia, and enrichment of Parabacteroides. LIMITATIONS: The studies in our review were heterogeneous in their participant population, dietary intake, type of ADs used, length and dosing of AD treatment, and frequency and time of fecal sample collection. CONCLUSION: ADs are associated with some changes to the gut microbiome. Future studies should evaluate the gut microbiome profiles between depressive disorder diagnoses that may reveal potential differences and predictors of AD response, as well as new combinatorial therapeutics with agents (e.g., specific-strain probiotic adjunctive treatment) that can ameliorate micro-composition gut dysbiosis.
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Microbiome composition and central serotonergic activity in patients with depression and type 1 diabetes.
The role of gut-brain axis functioning gains growing attention in research on the pathophysiology of major depressive disorders. Here, especially consequences of altered microbiota composition on tryptophan metabolism resulting in altered serotonergic neurotransmission in the central nervous system (CNS) have reached a central position. Previous research, however, mainly focused on either microbiota and peripheral serotonin levels or central serotonergic neurotransmission. The present study aimed to combine the analysis of microbiota composition and central serotonergic activity using a valid neurophysiological indicator. We recruited 19 adult patients with type 1 diabetes and depression (D + D; 7 males), 19 patients with type 1 diabetes (D-; 7 male), and 20 healthy participants (HC; 7 males). Next to the analysis of fecal microbiota regarding α- and β-diversity, the loudness dependence of auditory evoked potential (LDAEP) was investigated, a non-invasive measurement of central serotonergic activity. High α-diversity was associated with high LDAEP, i.e., low serotonergic activity, in patients with diabetes and additional depression. Furthermore, relative abundances of bacterial families belonging to Bacteroidetes, Proteobacteria and Firmicutes were shown to have an impact on central serotonergic activity. This finding was supported by a tendency indicating an association of central serotonergic activity with the Bacteroidetes-Firmicutes ratio in both patients' groups. Together, this data suggests that the guts' microbiota composition might play an important role in regulating the central serotonergic activity in the brain.
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Microbiome-Inflammation-Mitochondria Coupling in Neurodegeneration and Depression: An Integrative Opinion.
There is increasing evidence that gut microbiome dysbiosis, systemic inflammation, and mitochondrial dysfunction interact in ways that influence psychiatric and neurodegenerative disease vulnerability. Recent findings indicate that microbial signaling, inflammatory activation, and mitochondrial stress responses form dynamic bidirectional networks that may influence neurotransmission, neuroplasticity, metabolism, and behavior. This integrative opinion article distinguishes major depressive disorder (MDD), Parkinson's disease (PD), and Alzheimer's disease (AD) as mechanistically distinct disorders while proposing that they may share overlapping upstream modulatory pathways involving inflammation, microbial dysregulation, and mitochondrial dysfunction. Importantly, the microbiome-inflammation-mitochondria axis is presented as a disease-modifying and vulnerability-associated framework rather than a singular unifying etiology. Current limitations including reverse causation, microbiome heterogeneity, and differences in treatment responsiveness are also discussed.
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[Gut microbiota and depressive symptoms].
The gut microbiota is believed to affect a wide variety of mental disorders, including depression. The hypothesis involves bacterial signalling to the host through metabolic, endocrinal, immunologic and neuronal pathways. Few studies of patients with depression have shown altered microbiota profiles and increased levels of systemic endotoxin, which can be detected by leucocytes and result in expression of cytokines. Studies performed so far have lacked statistical power and provide no causal explanation for the gut-brain hypothesis. Further research into the matter is certainly warranted.
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A comprehensive analysis of the differential expression in the hippocampus of depression induced by gut microbiota compared to traditional stress.
Depression, which is a disease of heterogeneous etiology, is characterized by high disability and mortality rates. Gut microbiota are associated with the development of depression. To further explore any differences in the mechanisms of depression induced by gut microbiota and traditional stresses, as well as facilitate the development of microbiota-based interventions, a fecal microbiota transplantation (FMT) depression model was made. This was achieved by transplanting feces from major depressive disorder (MDD) patients into germ-free mice. Second, the mechanisms of the depression induced by gut microbiota were analyzed in comparison with those of the depression caused by different forms of stress. It turned out that mice exhibited depressive-like behavior after FMT. Then, PCR array analysis was performed on the hippocampus of the depressed mice to identify differentially expressed genes (DEGs). The KEGG analysis revealed that the pathways of depression induced by gut microbes are closely associated with immuno-inflammation. To determine the pathogenic pathways of physiological stress and psychological stress-induced depression, raw data was extracted from several databases and KEGG analysis was performed. The results from the analysis revealed that the mechanisms of depression induced by physiological and psychological stress are closely related to the regulation of neurotransmitters and energy metabolism. Interestingly, the immunoinflammatory response was distinct across different etiologies that induced depression. The findings showed that gut microbiota dysbiosis-induced depression was mainly associated with adaptive immunity, while physiological stress-induced depression was more linked to innate immunity. This study compared the pathogenesis of depression caused by gut microbiota dysbiosis, and physiological and psychological stress. We explored new intervention methods for depression and laid the foundation for precise treatment.