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Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model.
Postpartum depression (PPD) is a severe mental disorder that affects approximately 10---20% of women after childbirth. The precise mechanism underlying PPD pathogenesis remains elusive, thus limiting the development of therapeutics. Gut microbiota dysbiosis is considered to contribute to major depressive disorder. However, the associations between gut microbiota and PPD remain unanswered. Here, we established a mouse PPD model by sudden ovarian steroid withdrawal after hormone-simulated pseudopregnancy-human (HSP-H) in ovariectomy (OVX) mouse. Ovarian hormone withdrawal induced depression-like and anxiety-like behaviors and an altered gut microbiota composition. Fecal microbiota transplantation (FMT) from PPD mice to antibiotic cocktail-treated mice induced depression-like and anxiety-like behaviors and neuropathological changes in the hippocampus of the recipient mice. FMT from healthy mice to PPD mice attenuated the depression-like and anxiety-like behaviors as well as the inflammation mediated by the NOD-like receptor protein (NLRP)-3/caspase-1 signaling pathway both in the gut and the hippocampus, increased fecal short-chain fatty acids (SCFAs) levels and alleviated gut dysbiosis with increased SCFA-producing bacteria and reduced Akkermansia in the PPD mice. Also, downregulation of NLRP3 in the hippocampus mitigated depression-like behaviors in PPD mice and overexpression of NLRP3 in the hippocampal dentate gyrus induced depression-like behaviors in naïve female mice. Intriguingly, FMT from healthy mice failed to alleviate depression-like behaviors in PPD mice with NLRP3 overexpression in the hippocampus. Our results highlighted the NLRP3 inflammasome as a key component within the microbiota-gut-brain axis, suggesting that targeting the gut microbiota may be a therapeutic strategy for PPD.
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Bacteroides species differentially modulate depression-like behavior via gut-brain metabolic signaling.
Gut microbiome disturbances have been widely implicated in major depressive disorder (MDD), although the identity of causal microbial species and the underlying mechanisms are yet to be fully elucidated. Here we show that Bacteroides species enriched in the gut microbiome from MDD patients differentially impact the susceptibility to depressive behaviors. Transplantation of fecal microbiome from MDD patients into antibiotic-treated mice induced anxiety and despair-like behavior and impaired hippocampal neurogenesis. Colonization of Bacteroides fragilis, Bacteroides uniformis, and, to a lesser extent, Bacteroides caccae, but not Bacteroides ovatus, recapitulated the negative effects of MDD microbiome on behavior and neurogenesis. The varying impacts of Bacteroides species were partially explained by differential alternations of tryptophan pathway metabolites and neurotransmitters along the gut-brain axis. Notably, an intensified depletion of cerebral serotonin concurred with the enhanced susceptibility to depression. Together, these findings identify select Bacteroidetes species that contribute to depression susceptibility in mice by metabolic regulation along the gut-brain axis.
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Gut microbiome in adolescent depression.
OBJECTIVES: To examine the association of major depressive disorder (MDD) and selective serotonin reuptake inhibitor (SSRI) use with gut microbiome in older adolescents and younger adults. METHODS: Fifteen to 20-year-old participants within a month of starting an SSRI and unmedicated controls were enrolled in a longitudinal study. They underwent a diagnostic evaluation comprising self-completed and rater-administered questionnaires and clinical interview. They also provided a stool sample, which was stored at -80°C until DNA extraction. Microbial DNA was extracted with the MoBio PowerSoil kit, and the V4 region of the 16S rRNA was amplified and sequenced. Raw sequence data was processed with the LotuS pipeline. Only samples with no antibiotic exposure in the last 6 months and with >1000 quality filtered reads were included in the analysis. RESULTS: 160 participants (57.5% female, mean age 20.0±1.9 years, 29% taking SSRIs) were enrolled, comprising 110 MDD patients (60% in acute episode), 27 healthy controls, and 23 psychiatric controls. No significant group differences were observed in bacterial richness or alpha and beta diversity. Differential abundance analysis of bacterial taxa found no significant group differences at the phylum and genus levels. Neither being in a major depressive episode vs. remission nor using SSRIs was associated with differential bacterial composition. CONCLUSIONS: In this sizeable sample of older adolescents, neither MDD nor SSRI use was associated with differences in gut bacterial microbiome. In this age group, the bi-directional interaction between the gut bacteria and brain may be more nuanced than in adults, requiring further investigation.
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The gut-brain vascular axis in neuroinflammation.
The multifaceted microbiota characterizing our gut plays a crucial role in maintaining immune, metabolic and tissue homeostasis of the intestine as well as of distal organs, including the central nervous system. Microbial dysbiosis is reported in several inflammatory intestinal diseases characterized by the impairment of the gut epithelial and vascular barriers, defined as leaky gut, and it is reported as a potential danger condition associated with the development of metabolic, inflammatory and neurodegenerative diseases. Recently, we pointed out the strict connection between the gut and the brain via a novel vascular axis. Here we want to deepen our knowledge on the gut-brain axis, with particular emphasis on the connection between microbial dysbiosis, leaky gut, cerebral and gut vascular barriers, and neurodegenerative diseases. The firm association between microbial dysbiosis and impairment of the vascular gut-brain axis will be summarized in the context of protection, amelioration or boosting of Alzheimer, Parkinson, Major depressive and Anxiety disorders. Understanding the relationship between disease pathophysiology, mucosal barrier function and host-microbe interaction will foster the use of the microbiome as biomarker for health and disease as well as a target for therapeutic and nutritional advances.
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Toward a Deeper Understanding of Gut Microbiome in Depression: The Promise of Clinical Applicability.
The emergence of the coronavirus disease 2019 pandemic has dramatically increased the global prevalence of depression. Unfortunately, antidepressant drugs benefit only a small minority of patients. Thus, there is an urgent need to develop new interventions. Accumulating evidence supports a causal relationship between gut microbiota dysbiosis and depression. To advance microbiota-based diagnostics and therapeutics of depression, a comprehensive overview of microbial alterations in depression is presented to identify effector microbial biomarkers. This procedure generated 215 bacterial taxa from humans and 312 from animal models. Compared to controls, depression shows significant differences in β-diversity, but no changes in microbial richness and diversity. Additionally, species-specific microbial changes are identified like increased Eggerthella in humans and decreased Acetatifactor in rodent models. Moreover, a disrupted microbiome balance and functional changes, characterized by an enrichment of pro-inflammatory bacteria (e.g., Desulfovibrio and Escherichia/Shigella) and depletion of anti-inflammatory butyrate-producing bacteria (e.g., Bifidobacterium and Faecalibacterium) are consistently shared across species. Confounding effects of geographical region, depression type, and intestinal segments are also investigated. Ultimately, a total of 178 species and subspecies probiotics are identified to alleviate the depressive phenotypes. Current findings provide a foundation for developing microbiota-based diagnostics and therapeutics and advancing microbiota-oriented precision medicine for depression.
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The emerging role of the gut microbiome in depression: implications for precision medicine.
Major depressive disorder is a debilitating mental illness that seriously endangers human health. Its pathogenesis is highly complex, and traditional treatments face substantial challenges. A growing body of preclinical and clinical findings highlight the important role of the gut microbiome in the pathogenesis of depression and its potential as a diagnostic and therapeutic target. A deeper understanding of how the gut microbiome regulates depression will greatly enhance its clinical application, improve diagnostic and treatment strategies, and pave the way for microbiota-based precision medicine for depression. In this review, we summarize the depression-associated compositional and functional microbial alterations, delineate their mechanistic contributions to disease pathogenesis, and evaluate their potentiality as novel diagnostic biomarkers and treatment targets. Finally, we consider the future potential of utilizing the gut microbiome to advance precision medicine approaches for depression.
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Depression: A Gut "Microbiome" Feeling!
Burgeoning body of evidence from neuroscience is pouring in highlighting a potential association between gut microbiota with the pathophysiology of depression and anxiety. Manipulation of gut microbiota may be then useful to decode this role and to provide novel therapeutics for major depressive disorder (MDD), developing microbiota-related biomarkers to stratify patients at risk and to delineate more homogeneous biotypes of MDD.
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Diet, Stress and Mental Health.
INTRODUCTION: There has long been an interest in the effects of diet on mental health, and the interaction of the two with stress; however, the nature of these relationships is not well understood. Although associations between diet, obesity and the related metabolic syndrome (MetS), stress, and mental disorders exist, causal pathways have not been established. METHODS: We reviewed the literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress. RESULTS: Diet and obesity can affect mood through direct effects, or stress-related mental disorders could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or predisposition could lead to both obesity and stress-related mental disorders, such as depression and posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a treatment for depression. Bidirectional relationships between these different factors are also likely. Finally, there has been increased attention recently on the relationship between the gut and the brain, with the realization that the gut microbiome has an influence on brain function and probably also mood and behavior, introducing another way diet can influence mental health and disorders. Brain areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely play a role in mediating this relationship. CONCLUSIONS: Understanding the relationship between diet, stress and mood and behavior could have important implications for the treatment of both stress-related mental disorders and obesity.
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Inflammatory Depression-Mechanisms and Non-Pharmacological Interventions.
Treatment of depression is hampered by the failure to identify distinct symptom profiles with distinct pathophysiologies that differentially respond to distinct treatments. We posit that inflammatory depression is a meaningful depression subtype associated with specific symptoms and biological abnormalities. We review several upstream, potentially causative, mechanisms driving low-grade inflammation in this subtype of depression. We also discuss downstream mechanisms mediating the link between inflammation and symptoms of depression, including alterations in dopaminergic neurotransmission and tryptophan metabolism. Finally, we review evidence for several non-pharmacological interventions for inflammatory depression, including probiotics, omega-3 fatty acids, and physical exercise interventions. While some evidence suggests that these interventions may be efficacious in inflammatory depression, future clinical trials should consider enriching patient populations for inflammatory markers, or stratify patients by inflammatory status, to confirm or refute this hypothesis.
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EZH2-mediated H3K27me3 links microbial inosine loss to depression: a gut-brain epigenetic switch.
Background: Depression, the second most prevalent neurological disorder globally, affects over 300 million people and presents an urgent public health challenge. While gut microbiota dysbiosis is increasingly recognized as a key contributor to depression, the molecular mechanisms linking microbial imbalance to brain dysfunction remain poorly defined. Methods: We investigated the role of EZH2 in gut microbiota-induced depressive behaviors in mice using the chronic unpredictable mild stress (CUMS), fecal microbiota transplantation, and conditional knockout of EZH2. CUT&Tag sequencing was employed to analyze EZH2-mediated H3K27me3 epigenetic reprogramming. Untargeted metabolomics and luciferase reporter assays were used to identify metabolites that upregulate EZH2 expression. 16S rRNA sequencing combined with metabolic tracing was conducted to trace the microbial origin of inosine. Additionally, natural compound screening identified coumaric acid (CA) as a novel EZH2-targeting degrader. Results: Conditional knockout of neuronal Ezh2 abolishes microbiota-induced depressive behaviors and neuronal apoptosis. Mechanistically, reduced abundance of specific microbiota (f_Lachnospiraceae, f_Oscillospiraceae, and f_Erysipelotricaceae) leads to inosine depletion. This depletion subsequently elevates EZH2 transcriptional activity by increasing H3K9ac modification at its locus, mediated through attenuation of the A2aR-cAMP-PKA-CREB-HDAC3 signaling axis. Subsequently, EZH2 silences serotonergic synapse-related genes (e.g., Tph2, Htr2a, Htr6) via H3K27me3 reprogramming, ultimately driving depressive behaviors and neuronal apoptosis in mice. Importantly, CA is identified as a first-in-class EZH2 degrader that binds lysine residues K623/K646 and recruits UBE3A for proteasomal degradation. CA treatment restores synaptic integrity and reverses depressive behaviors with minimal toxicity. Conclusions: Collectively, these findings define a novel "microbiota-inosine-EZH2" axis in depression pathogenesis and highlight EZH2 degradation as a promising therapeutic strategy for microbiota-associated neuropsychiatric disorders.