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Acupuncture for Major Depressive Disorder: Exploring the Gut Microbiota as a Novel Therapeutic Pathway.
AIMS: This study investigates the efficacy of acupuncture at Baihui (GV20) and Zusanli (ST36) acupoints in alleviating depressive symptoms and elucidates the underlying mechanisms. METHODS: Sixty male C57BL/6J mice were subjected to an 8-week chronic unpredictable mild stress (CUMS) paradigm. Acupuncture was administered to two groups during the final 3 weeks: one under CUMS and the other without stress. Behavioral assessments, including the sucrose preference test and tail suspension test (TST), evaluated depression-like behaviors. 16S rRNA sequencing and non-targeted metabolomics analyzed gut microbiota and metabolites, respectively, with association analysis exploring the mechanistic pathways. RESULTS: Acupuncture significantly ameliorated CUMS-induced depression-like behaviors, restoring sucrose preference (from a significant reduction in CUMS, p < 0.001, to an increase in CUMS + AP, p = 0.035) and reducing immobility time in the TST (p = 0.045). 16S rRNA sequencing revealed that acupuncture partially restored the CUMS-disrupted Bacteroidetes/Firmicutes ratio by specifically decreasing the pathobiont Clostridium sp. A3LF 105b and increasing beneficial bacteria such as Faecalibacterium and Lachnospiraceae UCG 001. These microbial shifts were functionally linked to the elevation of the critical metabolite sphinganine 1-phosphate (S1P). Spearman correlation analysis revealed a negative correlation between Clostridium sp. A3LF 105b and S1P (p < 0.01, R < -0.52). The modulation of gut microbiota led to increased S1P, which in turn activated the "neuroactive ligand-receptor interaction" pathway, thereby restoring neuronal activity and alleviating depressive behavior. CONCLUSION: The study underscores the potential of acupuncture as an antidepressant treatment, highlighting its impact on gut microbiota and metabolic pathways in alleviating depressive symptoms.
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[Mechanisms by which the gut microbiota regulates depressive disorder via the tryptophan metabolic pathway].
The relationship between gut microbiota and depressive disorder has become a research focus in recent years. Within the microbiota-gut-brain axis, the gut microbiota influences the onset and progression of depressive disorder primarily through the tryptophan metabolic pathway. Tryptophan, an essential amino acid in humans, is subject to dual regulation by intestinal microorganisms, which modulate its metabolic balance via inflammatory stimulation and microbial metabolite production. In depression, excessive activation of the kynurenine branch of tryptophan metabolism leads to the accumulation of proinflammatory and neurotoxic metabolites, thereby exacerbating neuroinflammation in the brain. Intervention studies indicate that the antidepressant-like effects of probiotics and traditional Chinese medicine are associated with remodeling of the gut microbiota, restoration of tryptophan metabolic balance, and alleviation of neuroinflammation. Furthermore, targeted inhibition of kynurenine 3-monooxygenase can mitigate neuroinflammation by regulating microglial activity, thus improving depressive-like behaviors. In summary, the metabolite-inflammation axis represents a central node in the interaction regulation between tryptophan metabolism and the microbiota-gut-brain axis. This provides a theoretical foundation for developing novel therapeutic strategies targeting depression through modulation of gut microbiota-mediated tryptophan metabolism.
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The Microbiota-Gut-Brain Axis in the Pathophysiology of Major Depressive Disorder: A Mechanistic Review.
Major Depressive Disorder (MDD) is a globally prevalent and debilitating psychiatric condition whose pathophysiology remains incompletely understood. Emerging evidence compels a paradigm shift from a purely neurocentric model to one that incorporates the microbiota-gut-brain (MGB) axis, a complex bidirectional communication network. This review synthesizes current research to build a comprehensive mechanistic model of how disruptions within this axis contribute to the development and maintenance of MDD. We deconstruct the core communication pathways, beginning with the foundational state of gut dysbiosis and compromised intestinal barrier integrity observed in MDD patients. We then delve into the downstream consequences, examining how microbial metabolites, particularly short-chain fatty acids and products of tryptophan metabolism, act as critical signaling molecules. The review details how these signals are conveyed to the central nervous system (CNS) via direct neural pathways, including the enteric nervous system and the vagus nerve, and through systemic humoral and neuroimmune cascades. Specifically, we explore the roles of gut-derived inflammation, microglial activation, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. By integrating these pathways, we present a cohesive model wherein gut-derived pathology drives central neuroinflammation, neurotransmitter disruption, and impaired neuroplasticity, culminating in the clinical manifestation of MDD. This MGB axis framework not only provides a more holistic understanding of MDD as a systemic illness but also illuminates novel targets for diagnostic biomarkers and therapeutic interventions.
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Ketogenic diet for depression: A potential dietary regimen to maintain euthymia?
Approximately 30% of patients with major depressive disorder (MDD) present resistance to current pharmacological therapies. There is the possibility that an appropriate nutritional regimen can maintain euthymia. Poor dietary pattern and lack of nutritional knowledge are common among today's population; nutrient-rich foods are being replaced by highly processed foods that lead to a higher risk of developing chronic diseases such as metabolic syndrome, hypercholesterolemia, and diabetes. There is growing evidence of the beneficial role of vitamins and dietary supplements for improving symptoms in a range of affective disorders by regulating the gut microbiome, gut-brain axis, and neurotransmitter levels. Reduced GABA neurotransmission is regularly observed in MDD. Moreover, positive allosteric GABA modulators (i.e benzodiazepines) are widely prescribed to alleviate depression symptoms, but their use needs to be limited, as it can lead to addiction. An alternative option may be the adherence to a ketogenic diet, which consists of low-carbohydrate, moderate-protein, and high-fat intake. It is mainly known for its beneficial role in weight-loss, refractory epilepsy treatment, and balancing glucose levels. A ketogenic diet can also increase GABA levels to aid the mechanism of action of monoaminergic drugs. Thus, it could potentially be used in the treatment for affective disorders due to its potential role in GABA/glutamate balance. While more research is needed before this regimen can be regularly recommended to patients, here we discuss evidence that may encourage physicians to prescribe ketogenic diet as an adjuvant for patients receiving psychotherapy and pharmacology.
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Medication use is associated with distinct microbial features in anxiety and depression.
This study investigated the relationship between gut microbiota and neuropsychiatric disorders (NPDs), specifically anxiety disorder (ANXD) and/or major depressive disorder (MDD), as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV or V criteria. The study also examined the influence of medication use, particularly antidepressants and/or anxiolytics, classified through the Anatomical Therapeutic Chemical (ATC) Classification System, on the gut microbiota. Both 16S rRNA gene amplicon sequencing (16S) and shallow shotgun sequencing (WGS) were performed on DNA extracted from 666 fecal samples from the Tulsa-1000 and Neurocomputational Mechanisms of Affiliation and Personality Study Center for Biomedical Research Excellence (NeuroMAP CoBRE) cohorts. The results highlight the significant influence of medication use; antidepressant use is associated with significant differences in gut microbiota beta diversity and has a larger effect size than NPD diagnosis. Next, specific microbes were associated with ANXD and MDD, highlighting their potential for non-pharmacological intervention. Finally, the study demonstrated the capability of Random Forest classifiers to predict diagnoses of NPD and medication use from microbial profiles, suggesting a promising direction for the use of gut microbiota as biomarkers for NPD. Though the effect sizes were larger in females than males, similar trends emerged for both sexes. These findings encourage future research on the gut microbiota's role in NPD and its interactions with pharmacological treatments.
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Distinct effects of different Bacteroides strains on depressive-like behavior via a gut-Th1/Th17 cells-brain axis.
Extensive evidence links gut microbiota to the pathogenesis of major depressive disorder (MDD), yet the specific microbial species involved remain unclear. Here, we identify distinct roles of three Bacteroides species-B. uniformis, B. vulgatus, and B. thetaiotaomicron-in depression. B. uniformis increases susceptibility to depression in mice, significantly enhances Th17 cell differentiation in vivo and in vitro, and upregulates hippocampal IL-17A level. However, treatment with SR1001, a Th17 cell inhibitor, alleviates B. uniformis-induced depressive-like behaviors. Conversely, B. thetaiotaomicron and B. vulgatus attenuate depressive behaviors in mice, significantly suppresse the differentiation of Th1 and Th17 cells in vivo, and reduce the levels of hippocampal cytokines, including IL-17A, IFN-γ, and TNF-α. Clinical analyses reveal increased Th1 and Th17 cells in MDD patients, correlating with depression severity. B. uniformis is enriched in MDD fecal samples and positively associated with Th17 levels, whereas B. thetaiotaomicron showes an inverse correlation. Mechanistically, targeted metabolomic shows that B. uniformis reduces butyric acid and cholesterol sulfate, whereas B. thetaiotaomicron increases butyric acid, propionic acid, and biotin, all of which are linked to Th1 and Th17 regulation. These findings highlight the role of Bacteroides species in depression via a gut-Th1/Th17 cells-brain axis, providing mechanistic insights and ideas for therapeutic strategies.
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Brain-gut-microbiota axis: challenges for translation in psychiatry.
PURPOSE: The accruing data linking the gut microbiome to the development and function of the central nervous system has been proposed as a paradigm shift in neuroscience. The gut microbiota can communicate with the brain via neuroimmune, neuroendocrine, and neural pathways comprising the brain-gut-microbiota axis. Dysfunctional neuroimmune pathways are implicated in stress-related psychiatric disorders. METHODS: Using depression as our primary example, we review both the preclinical and clinical evidence supporting the possible role played by the gut microbiota in stress-related psychiatric disorders. We consider how this can inform future treatment strategies and outline the challenges and necessary studies for moving the field forward. RESULTS: The role played by the gut microbiota has not been fully elucidated in psychiatric populations. Although tempting to speculate that psychiatric patients may benefit from therapeutic modulation of the brain-gut-microbiota axis, the translational applications of the results obtained in rodent studies have yet to be demonstrated. CONCLUSIONS: Evidence of altered gut microbiota composition and function in psychiatric patients is limited and cannot be regarded as proven. Moreover the efficacy of targeting the gut microbiota has not yet been established, and needs further investigation.
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Role of Opioidergic System in Regulating Depression Pathophysiology.
BACKGROUND: There is a clear clinical need for a better understanding of the biological underpinnings of major depressive disorder (MDD), allowing for the development of a treatment that is targeted to pathophysiology. Recent data indicate a role for the endogenous opioidergic system in MDD. This article reviews the roles and physiological interactions of the endogenous opioidergic system in the pathophysiology and heterogeneity of MDD. METHODS: Articles on the pathophysiology of MDD, as well as on the endogenous opioidergic system and mitochondrial function, form the basis of this review article. RESULTS: The endogenous opioidergic system is intimately linked to wider MDD pathophysiology, including alterations in the gut microbiome, gut permeability, circadian rhythm, amygdala-prefrontal cortex interactions, and mitochondrial function. A decrease in the μ-/κ-opioid receptor ratio is an important mediator of the changes in mood in MDD, with effects not only on neurons, but also on glia and immune cells. CONCLUSION: The endogenous opioidergic system is intimately interwoven with MDD pathophysiology and provides a relevant target for novel treatment development, as well as providing a focus for the integration of wider MDD pathophysiology.
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Taxonomic and Metabolic Signatures of Gut Microbiota for Assessing the Severity of Depression and Anxiety in Major Depressive Disorder Patients.
Major depressive disorder (MDD) is a heterogeneous mental disorder for which the precise assessment of symptom severity remains challenging. Studies have consistently found that the microbiota-gut-brain (MGB) axis is profoundly altered in MDD, but whether MGB-relevant clinical parameters are applicable to depression subphenotyping remains largely unexplored. In this prospective study, we assessed the taxonomic and metabolic signatures of fecal microbiota from 45 unmedicated MDD patients and explored their associations with the severity of depression and anxiety symptoms as measured by Hamilton depression scale-17 (HAMD-17) and Hamilton anxiety scale-14 (HAMA-14), respectively. The global microbial compositions of MDD patients with mild, moderate and severe symptoms were largely similar. Nevertheless, multiple discriminative bacterial taxa could be identified among the subgroups across the genus to species level. The abundance of fecal Streptococcus was highly correlated with both HAMD and HAMA scores. Patients with severe depression symptoms showed significantly higher abundance of Phascolarctobacterium and Akkermansia, while enrichment of Akkermansia, Coprococcus and Streptococcus were observed with severe anxiety symptoms. In addition, fecal microbial metabolite indole-3-carboxyaldehyde proved useful to discriminate the severity of depression or anxiety symptoms. Together, our results support the utility of microbial taxa and metabolites as potential MGB-based biomarker panel for stratifying the symptom severity of MDD patients.
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Reductions in anti-inflammatory gut bacteria are associated with depression in a sample of young adults.
We assessed the gut microbiota of 90 American young adults, comparing 43 participants with major depressive disorder (MDD) and 47 healthy controls, and found that the MDD subjects had significantly different gut microbiota compared to the healthy controls at multiple taxonomic levels. At the phylum level, participants with MDD had lower levels of Firmicutes and higher levels of Bacteroidetes, with similar trends in the at the class (Clostridia and Bacteroidia) and order (Clostridiales and Bacteroidales) levels. At the genus level, the MDD group had lower levels of Faecalibacterium and other related members of the family Ruminococcaceae, which was also reduced relative to healthy controls. Additionally, the class Gammaproteobacteria and genus Flavonifractor were enriched in participants with MDD. Accordingly, predicted functional differences between the two groups include a reduced abundance of short-chain fatty acid production pathways in the MDD group. We also demonstrated that the magnitude of taxonomic changes was associated with the severity of depressive symptoms in many cases, and that most changes were present regardless of whether depressed participants were taking psychotropic medications. Overall, our results support a link between MDD and lower levels of anti-inflammatory, butyrate-producing bacteria, and may support a connection between the gut microbiota and the chronic, low-grade inflammation often observed in MDD patients.