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Are conventional antidepressants enough? The gut microbiome and nanocarrier-based delivery systems as future prospects for depression treatment.
Depression is the leading cause of disability worldwide and thus a major contributor to the economic burden of disease. In addition to genetic and epigenetic factors, sustained psychological stress linked to modern lifestyles (often characterized by high social expectations, elevated workload and increasing financial needs) may trigger psychiatric diseases such as depression. The effective treatment of this psychiatric condition represents one of the major challenges of our time, due to its skyrocketing increase in prevalence. While conventional antidepressants often provide low response rates and have frequent adverse effects, emerging research is revealing novel and more efficient therapeutic approaches. Notably, the bacteria that populates our intestinal tract, also known as the gut microbiota, is highly susceptible to stress and other factors associated with depression. Therefore, gut microbiota-targeting interventions based on lifestyle modifications or direct supplementation with biotherapeutic agents are being proposed as monotherapy or as adjuvants to conventional treatments. In addition, novel delivery systems, such as nanocarriers, for current antidepressants are being explored to improve drug bioavailability and therapeutic efficiency. This review summarizes the role of the gut microbiota in the pathogenesis of depression and its link with current antidepressant treatments. Furthermore, it explores how strategies like nanoparticle-based delivery systems are paving the way for the next generation of treatments.
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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.
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The Power of Psychobiotics in Depression: A Modern Approach through the Microbiota-Gut-Brain Axis: A Literature Review.
The microbiota-gut-brain (MGB) axis is a complex communication network linking the gut, microbiota, and brain, influencing various aspects of health and disease. Dysbiosis, a disturbance in the gut microbiome equilibrium, can significantly impact the MGB axis, leading to alterations in microbial composition and function. Emerging evidence highlights the connection between microbiota alterations and neurological and psychiatric disorders, including depression. This review explores the potential of psychobiotics in managing depressive disorders, emphasizing their role in restoring microbial balance and influencing the MGB axis. Psychobiotics exhibit positive effects on the intestinal barrier, immune response, cortisol levels, and the hypothalamic-pituitary-adrenal (HPA) axis. Studies suggest that probiotics may serve as an adjunct therapy for depression, especially in treatment-resistant cases. This review discusses key findings from studies on psychobiotics interventions, emphasizing their impact on the gut-brain axis and mental health. The increasing acceptance of the expanded concept of the MGB axis underscores the importance of microorganisms in mental well-being. As our understanding of the microbiome's role in health and disease grows, probiotics emerge as promising agents for addressing mental health issues, providing new avenues for therapeutic interventions in depressive disorders.
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Gut microbiome signatures associated with depression and obesity.
UNLABELLED: Depression and obesity are highly comorbid and likely involve common risk factors and pathophysiological mechanisms, which could crosslink to gut microbiome dysfunction. Here, we performed a case-control study with a total of 105 subjects, 43 with major depressive disorder (MDD) and 62 non-depressed controls free from psychiatric comorbidities, to identify gut microbiome signatures associated with MDD and dissect its relation to body mass index (BMI) and lifestyle (diet and exercise). We performed shotgun metagenomics, followed by taxonomic and functional annotations. Using different machine learning methods, we were able to classify subjects into depressed and non-depressed controls with a balanced accuracy of 0.90 and into depressed or non-depressed and normal weight or overweight with a balanced accuracy of 0.78 based solely on taxonomic profiles. We identify novel bacterial taxa associated with depression, including reductions in Butyrivibrio hungatei and Anaerocolumna sedimenticola, and also replicate previously reported associations, such as decreased Faecalibacterium prausnitzii in patients with MDD. Functional annotation of metagenomes shows differences in pathways linked to the synthesis of fundamental nutrients, which have been associated with diet, as well as inflammation. Strikingly, we found an increase in tryptophan degradation and a decrease in queuosine synthesis pathways, both of which are directly related to a decrease in monoaminergic neurotransmitter availability. Additionally, our functional analysis shows that most of the functions that are more abundant in controls than in depressed subjects are encoded by F. prausnitzii. These findings reveal distinct microbial and functional signatures associated with depression, including taxa and pathways linked to neurotransmitter metabolism and independent of other covariates. This suggests that gut microbiome profiling could support diagnosis and the development of gut-directed depression treatments. IMPORTANCE: This study identifies gut microbiome signatures that are predictive of major depressive disorder (MDD) and explores their links to body mass index (BMI). We uncover bacterial species and metabolic pathways that are associated with MDD, some of them related to neurotransmitter metabolism and inflammation. Among the differences identified, depletion of Faecalibacterium prausnitzii stands out as an important feature in the MDD microbiome, which suggests the possible use of this species to improve depression symptoms. Importantly, we demonstrate shared microbiome features between MDD and BMI, suggesting common underlying mechanisms. This research not only provides a framework for developing microbiome-based diagnostics but also informs future stratified interventions targeting gut microbial functions to improve mental health outcomes.
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Inflammation: depression fans the flames and feasts on the heat.
Depression and inflammation fuel one another. Inflammation plays a key role in depression's pathogenesis for a subset of depressed individuals; depression also primes larger cytokine responses to stressors and pathogens that do not appear to habituate. Accordingly, treatment decisions may be informed by attention to questions of how (pathways) and for whom (predispositions) these links exist, which are the focus of this article. When combined with predisposing factors (moderators such as childhood adversity and obesity), stressors and pathogens can lead to exaggerated or prolonged inflammatory responses. The resulting sickness behaviors (e.g., pain, disturbed sleep), depressive symptoms, and negative health behaviors (e.g., poor diet, a sedentary lifestyle) may act as mediating pathways that lead to further, unrestrained inflammation and depression. Depression, childhood adversity, stressors, and diet can all influence the gut microbiome and promote intestinal permeability, another pathway to enhanced inflammatory responses. Larger, more frequent, or more prolonged inflammatory responses could have negative mental and physical health consequences. In clinical practice, inflammation provides a guide to potential targets for symptom management by signaling responsiveness to certain therapeutic strategies. For example, a theme across research with cytokine antagonists, omega-3 fatty acids, celecoxib, and exercise is that anti-inflammatory interventions have a substantially greater impact on mood in individuals with heightened inflammation. Thus, when inflammation and depression co-occur, treating them in tandem may enhance recovery and reduce the risk of recurrence. The bidirectional links between depression, inflammation, and disease suggest that effective depression treatments could have a far-reaching impact on mood, inflammation, and health.
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5-HT attenuates chronic stress-induced cognitive impairment in mice through intestinal flora disruption.
BACKGROUND: The microbiota-gut-brain axis plays an important role in the development of depression. The aim of this study was to investigate the effects of 5-HT on cognitive function, learning and memory induced by chronic unforeseeable mild stress stimulation (CUMS) in female mice. CUMS mice and TPH2 KO mice were used in the study. Lactococcus lactis E001-B-8 fungus powder was orally administered to mice with CUMS. METHODS: We used the open field test, Morris water maze, tail suspension test and sucrose preference test to examine learning-related behaviours. In addition, AB-PAS staining, immunofluorescence, ELISA, qPCR, Western blotting and microbial sequencing were employed to address our hypotheses. RESULTS: The effect of CUMS was more obvious in female mice than in male mice. Compared with female CUMS mice, extracellular serotonin levels in TPH2 KO CUMS mice were significantly reduced, and cognitive dysfunction was aggravated. Increased hippocampal autophagy levels, decreased neurotransmitter levels, reduced oxidative stress damage, increased neuroinflammatory responses and disrupted gut flora were observed. Moreover, L. lactis E001-B-8 significantly improved the cognitive behaviour of mice. CONCLUSIONS: These results strongly suggest that L. lactis E001-B-8 but not FLX can alleviate rodent depressive and anxiety-like behaviours in response to CUMS, which is associated with the improvement of 5-HT metabolism and modulation of the gut microbiome composition.
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Gut microbiome promotes mice recovery from stress-induced depression by rescuing hippocampal neurogenesis.
Studies from rodents to primates and humans indicate that individuals vary in how resilient they are to stress, and understanding the basis of these variations may help improve treatments for depression. Here we explored the potential contribution of the gut microbiome to such variation. Mice were exposed to chronic unpredictable mild stress (CUMS) for 4 weeks then allowed to recover for 3 weeks, after which they were subjected to behavioral tests and categorized as showing low or high stress resilience. The two types of mouse were compared in terms of hippocampal gene expression using RNA sequencing, fecal microbiomes using 16S RNA sequencing, and extent of neurogenesis in the hippocampus using immunostaining of brain sections. Fecal microbiota were transplanted from either type of mouse into previously stress-exposed and stress-naïve animals, and the effects of the transplantation on stress-induced behaviors and neurogenesis in the hippocampus were examined. Finally, we blocked neurogenesis using temozolomide to explore the role of neurogenesis promoted by fecal microbiota transplantation in enhancing resilience to stress. Results showed that highly stress-resilient mice, but not those with low resilience, improved significantly on measures of anhedonia, behavioral despair, and anxiety after 3-week recovery from CUMS. Their feces showed greater abundance of Lactobacillus, Bifidobacterium and Romboutsia than feces from mice with low stress resilience, as well as lower abundance of Staphylococcus, Psychrobacter and Corynebacterium. Similarly, highly stress-resilient mice showed greater neurogenesis in hippocampus than animals with low stress resilience. Transplanting fecal microbiota from mice with high stress resilience into previously CUMS-exposed recipients rescued neurogenesis in hippocampus, facilitating recovery from stress-induced depression and cognitive decline. Blockade of neurogenesis with temozolomide abolished recovery of recipients from CUMS-induced depression and cognitive decline in mice transplanted with fecal microbiota from mice with high stress resilience. In conclusion, our results suggested that remodeling of the gut microbiome after stress may reverse stress-induced impairment of hippocampal neurogenesis and thereby promote recovery from stress-induced depression.
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Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials.
With growing interest in the gut microbiome, prebiotics and probiotics have received considerable attention as potential treatments for depression and anxiety. We conducted a random-effects meta-analysis of 34 controlled clinical trials evaluating the effects of prebiotics and probiotics on depression and anxiety. Prebiotics did not differ from placebo for depression (d = -.08, p = .51) or anxiety (d = .12, p = .11). Probiotics yielded small but significant effects for depression (d = -.24, p < .01) and anxiety (d = -.10, p = .03). Sample type was a moderator for probiotics and depression, with a larger effect observed for clinical/medical samples (d = -.45, p < .001) than community ones. This effect increased to medium-to-large in a preliminary analysis restricted to psychiatric samples (d = -.73, p < .001). There is general support for antidepressant and anxiolytic effects of probiotics, but the pooled effects were reduced by the paucity of trials with clinical samples. Additional randomized clinical trials with psychiatric samples are necessary fully to evaluate their therapeutic potential.
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Stress and the gut microbiota-brain axis.
Stress is a nonspecific response of the body to any demand imposed upon it, disrupting the body homoeostasis and manifested with symptoms such as anxiety, depression or even headache. These responses are quite frequent in the present competitive world. The aim of this review is to explore the effect of stress on gut microbiota. First, we summarize evidence of where the microbiota composition has changed as a response to a stressful situation, and thereby the effect of the stress response. Likewise, we review different interventions that can modulate microbiota and could modulate the stress according to the underlying mechanisms whereby the gut-brain axis influences stress. Finally, we review both preclinical and clinical studies that provide evidence of the effect of gut modulation on stress. In conclusion, the influence of stress on gut microbiota and gut microbiota on stress modulation is clear for different stressors, but although the preclinical evidence is so extensive, the clinical evidence is more limited. A better understanding of the mechanism underlying stress modulation through the microbiota may open new avenues for the design of therapeutics that could boost the pursued clinical benefits. These new designs should not only focus on stress but also on stress-related disorders such as anxiety and depression, in both healthy individuals and different populations.