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Microbes, mood, and metabolism/obesity: Pharmacological insights into the gut-obesity-depression triad.
The global rise in obesity and depression, two highly prevalent and often comorbid disorders has intensified interest in the gut–brain axis as a shared biological link. Mounting evidence indicates that the gut microbiota profoundly influences both metabolic and neuropsychiatric regulation, positioning it as a promising therapeutic target for these interconnected conditions. This review explores the complex interactions among microbial dysbiosis, host metabolism, and mood regulation, emphasizing pharmacological strategies that harness this triad for treatment. Gut-derived hormones such as glucagon-like peptide-1 (GLP-1) and microbiome-produced metabolites, including short-chain fatty acids (SCFAs) and bile acids, have demonstrated potential to modulate appetite, insulin sensitivity, inflammation, and brain function. GLP-1 receptor agonists like semaglutide originally developed for diabetes and obesity also exhibit antidepressant properties, highlighting their dual therapeutic promise. Emerging microbiome-based interventions, such as precision probiotics, engineered psychobiotics, and fecal microbiota transplantation (FMT), are being investigated to restore microbial balance and improve both metabolic and mood outcomes. Furthermore, combination therapies pairing microbiota-targeted agents with conventional antidepressants or anti-obesity drugs may offer synergistic benefits, enhance efficacy while minimize adverse effects. Despite this promise, significant challenges remain, including ensuring safety, understanding long-term impacts, navigating regulatory hurdles for live biotherapeutics, and addressing ethical concerns about altering the human microbiome. A deeper understanding of the gut–microbiome–brain axis may ultimately enable personalized, microbiota-guided therapies that treat both the physiological and psychological dimensions of obesity and depression, marking a major step toward holistic and precision medicine.
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Dietary Capsaicin Exacerbates Gut Microbiota Dysbiosis and Mental Disorders in Type 1 Diabetes Mice.
Background/Objectives: Diabetes mellitus is often accompanied by mental health complications, including anxiety, depression, and cognitive decline. Recent research suggested that capsaicin, the active component of chili peppers, may influence mental health. This study aimed to determine the effect of dietary capsaicin on mental disorders in a type 1 diabetes (T1D) mouse model, while also exploring the potential involvement of the microbiota-gut-brain axis. Methods: We induced T1D in mice using streptozotocin (STZ) and administered a diet supplemented with 0.005% capsaicin for five weeks. Behavioral assessments, including the open field test (OFT), tail suspension test (TST), forced swimming test (FST), elevated plus maze (EPM) test, and Morris water maze (MWM) test, were conducted to evaluate depressive and anxiety-like behaviors as well as cognitive function. Targeted and untargeted metabolomics analyses were performed to assess neurotransmitter levels in the hippocampus and serum metabolites, while 16S rRNA sequencing was utilized to analyze gut microbiota composition. Intestinal barriers were determined using western blot detection of the tight junction proteins ZO-1 and occludin. Results: Dietary capsaicin exacerbated anxiety and depressive-like behaviors along with cognitive declines in T1D mice. Capsaicin reduced gut microbiota diversity and levels of beneficial bacteria, while broad-spectrum antibiotic treatment further intensified anxiety and depression behaviors. Metabolomic analysis indicated that capsaicin disrupted metabolic pathways related to tryptophan and phenylalanine, leading to decreased neuroprotective metabolites, such as kynurenic acid, hippurate, and butyric acid. Additionally, capsaicin diminished the expression of ZO-1 and occludin, indicating increased intestinal permeability. Conclusions: Dietary capsaicin aggravates gut microbiota and metabolic disturbances in diabetic mice, thereby worsening anxiety, depression, and cognitive decline.
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Alterations in Gut Microbiota and Serum Metabolome Are Associated with Postpartum Depression.
Background: Postpartum depression (PPD) is a prevalent and debilitating disorder, with increasing evidence implicating the gut microbiota-brain axis. However, integrated alterations in gut microbiota and circulating metabolites in PPD remain insufficiently characterized. Methods: Fecal and serum samples were collected from patients with PPD and healthy controls (HC). Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17). Gut microbiota was analyzed by 16S rRNA sequencing, and serum metabolites were profiled using untargeted LC-MS-based metabolomics. Spearman correlation and receiver operating characteristic (ROC) analyses were performed. Results: A total of 63 participants (42 PPD, 21 HC) were included. Significant alterations in gut microbial composition were observed in PPD, including decreased Faecalibacterium and Akkermansia and increased Ralstonia and Fusobacterium. Candidate differential serum metabolic features, including LPE-related and energy-metabolism-related features, were identified. Exploratory correlation analyses suggested distinct microbiota-metabolite association patterns, and several microbial taxa and serum metabolic features were associated with HAMD-17 scores. ROC analysis showed that several taxa and metabolic features exhibited preliminary discriminative performance with this cohort, although further validation is required. Conclusions: PPD was associated with alterations in gut microbiota composition and exploratory circulating metabolite profiles, potentially involving lipid dysregulation, neuroinflammation, steroid-related metabolism, and neurotoxicity-related pathways. The identified taxa and putatively annotated metabolites should be regarded as exploratory PPD-associated candidates rather than validated biomarkers or mechanistic mediators. Further validation in larger, independent cohorts is warranted. These findings may also inform future microbiota- and nutrition-oriented strategies for postpartum mental health management.
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Leveraging the microbiome to understand clinical heterogeneity in depression: findings from the T-RAD study.
Alterations in the gut microbiome have been linked to a variety of mental illnesses including anxiety and depression. This study utilized advanced bioinformatics tools that integrated both the compositional and community nature of gut microbiota to investigate how gut microbiota influence clinical symptoms in a sample of participants with depression. Gut microbiota of 179 participants with major depressive disorder (MDD) in the Texas Resilience Against Depression (T-RAD) study were analyzed by 16S rRNA gene sequencing of stool samples. Severity of anxiety, depression, and anhedonia symptoms were assessed with General Anxiety Disorder - 7 item scale, Patient Health 9-item Questionnaire, and Dimensional Anhedonia Rating Scale, respectively. Using weighted correlation network analysis, a data-driven approach, three co-occurrence networks of bacterial taxa were identified. One of these co-occurrence networks was significantly associated with clinical features including depression and anxiety. The hub taxa associated with this co-occurrence module -one Ruminococcaceae family taxon, one Clostridiales vadinBB60 group family taxon, and one Christencenellaceae family taxon- were connected to several additional butyrate-producing bacteria suggesting that deficits in butyrate production may contribute to clinical symptoms. Therefore, by considering the community nature of the gut microbiome in a real world clinical sample, this study identified a gut microbial co-occurrence network that was significantly associated with clinical anxiety in a cohort of depressed individuals.
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Kai-Xin-San, an ancient herbal mixture for anti-depression, mitigates the fluoxetine-induced gut dysbiosis and intestinal damage in chronic unpredictable mild stressed mice.
ETHNOPHARMACOLOGICAL RELEVANCE: The gut microbiome plays a crucial role in the pathology of depression. The intestinal dysbiosis associated with prolonged use of antidepressants, such as fluoxetine, can adversely affect the efficacy of these medications. Kai-Xin-San (KXS), a traditional Chinese herbal decoction, has been utilized to treat mental disorders with a long history in China. The modulation of the gut microbiome by KXS could underlie its antidepressant effect. In the context of combining with fluoxetine, KXS could potentially mitigate fluoxetine-associated intestinal side effects during depression treatment. AIM OF THE STUDY: This study investigates the impact of KXS on the gut of depressive mice, with a particular emphasis on its potential to mitigate fluoxetine-induced intestinal side effects. MATERIALS AND METHODS: A high dose of fluoxetine was applied to the chronic unpredictable mild stress (CUMS)-induced mice, alone or in combination with KXS. Behavior tests were conducted to confirm the anti-depressant efficiencies. The feces of mice were collected and subjected to 16S rDNA and metagenomic sequencing. The gastrointestinal morphology and functions were assessed. The potential mechanistic action of KXS on alleviating the intestinal dysbiosis was probed. RESULTS: Notable imbalance of microbiome and disruption of intestinal barrier were observed in CUMS mice. The intake of fluoxetine exacerbated the dysbiosis, as evidenced by the increased ratio of Firmicutes/Bacteroidetes and the elevated abundance of antibiotic-resistant genes in the gut microbiome. In addition, fluoxetine treatment further compromised the intestinal integrity and functions. Significantly, KXS treatment effectively mitigated the impairment of intestinal barrier induced by fluoxetine. These protective effects appeared to be mediated through multiple mechanisms, including the restoration of microbial homeostasis and the direct cytoprotective action on intestinal epithelial cells. CONCLUSIONS: These findings particularly provide support for the combined usage of KXS and fluoxetine in depression treatment.
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Depression Promotes the Onset of Irritable Bowel Syndrome through Unique Dysbiosis in Rats.
BACKGROUND/AIMS: Although studies using conventional animal models have shown that specific stressors cause irritable bowel syndrome (IBS), it is unclear whether depression itself causes IBS. Our aim was to establish a rat model to determine if depression itself promotes the onset of IBS and to elucidate the role of gut microbiota in brain-gut axis pathogenesis during coincident depression and IBS. METHODS: Rat models of depression were induced using our shuttle box method of learned helplessness. Visceral hypersensitivity was evaluated by colorectal distension (CRD) to diagnose IBS. Gut microbiota compositions were analyzed using high-throughput sequencing. In the subanalysis of rats without depression-like symptoms, rats with posttraumatic stress disorder (PTSD) were also examined. RESULTS: The threshold value of CRD in depressed rats was significantly lower than that in control rats. Microbial community analysis of cecal microbiota showed that the relative abundance of Clostridiales incertae sedis, the most prevalent microbe, was significantly lower in depressed rats than in control rats. The distribution pattern of the microbiota clearly differed between depressed rats and control rats. Neither visceral hypersensitivity nor the composition of gut microbiota was altered in rats with PTSD-like phenotypes. CONCLUSIONS: Our rat model of depression is useful for clarifying the effect of depression on IBS and suggests that depression itself, rather than specific stressors, promotes the onset of IBS. Further, we provided evidence that various psychiatric diseases, viz., depression and PTSD, are associated with unique gut microbiota profiles, which could differentially affect the onset and progression of coincident IBS.
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Decoding the Protective Mechanisms of Rosa roxburghii Fermented Juice against CUMS-Induced Depression-like Behaviors: Insights from Gut Microbiota and Neuroinflammation.
Depression, recognized for its complex pathophysiology, remains a prevalent psychiatric disorder. The gut-brain axis is increasingly implicated in the pathophysiology of depressive symptoms, highlighting it as a promising intervention target. This study evaluated the protective effects of Rosa roxburghii fermented juice (RRFJ) in a chronic unpredictable mild stress (CUMS) mouse model. Results showed that RRFJ pretreatment significantly mitigated CUMS-induced depressive-like behaviors and hippocampal damage in C57BL/6J mice. Mechanistic investigations revealed that RRFJ induced remodeling of the gut microbiota characterized by an increased Firmicutes-to-Bacteroidetes ratio. This enhanced intestinal barrier integrity by reducing gut-derived lipopolysaccharide and upregulating tight junction proteins, ultimately resulting in decreased neuroinflammation in the hippocampus. Furthermore, RRFJ pretreatment modulated host metabolic profiles in plasma and brain tissue. In conclusion, RRFJ mitigates depressive-like behaviors, highlighting its preventive potential via mechanisms, including gut microbiota modulation, neuroinflammation suppression, and metabolic shifts in both plasma and brain.
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Alteration of gut microbiota in post-stroke depression patients with Helicobacter pylori infection.
BACKGROUND: Several studies have identified an association between the gut microbiome and post-stroke depression(PSD), and Helicobacter pylori(H. pylori) infection cause significant alterations in the composition of the gastrointestinal microbiome. However, evidence regarding the role of the H. pylori infection in promoting PSD is still lacking. Here, we conducted a retrospective study to explore risk factors associated with PSD. METHODS: Patients with cerebral infarction were consecutively enrolled from December 2021 to October 2022. The diagnosis of PSD is based on the DSM-V criteria, and the Hamilton Depression Rating Scale(HAMD) was used to identify patients with PSD. White matter lesions were evaluated using magnetic resonance imaging(MRI) and H. pylori infection was detected by 13C-urea breath test. Further, 16S rRNA gene sequencing was used to evaluate the changes in gut microbiota composition of fecal samples from PSD patients. The concentration of short-chain fatty acids(SCFAs) was determined by gas chromatography-mass spectrometry(GC-MS). RESULTS: Multivariate regression analysis showed that deep white matter lesions(DWMLs) [odds ratio(OR) 3.382, 95% confidence interval(CI) 1.756-6.512; P = 0.001] and H. pylori infection(OR 2.186, 95% CI 1.149-4.159; P = 0.017) were the independent risk factors for PSD. Patients with H. pylori infection had more severe depressive symptoms than patients without infection. Intestinal microbiota was significantly different between H. pylori-positive PSD[H. pylori(+)] patients and H. pylori-negative PSD[H. pylori (-)] patients. Fecal SCFAs concentrations were significantly reduced in the H. pylori(+) group compared to the negative ones. CONCLUSION: DWMLs and H. pylori infection may play important roles in the development of PSD. H. pylori infection is likely to be involved in the pathogenesis of PSD by altering the intestinal flora.
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Lactiplantibacillus plantarum KLDS1.0344 ameliorates depressive-like behavior in CUMS mice: integrative multi-omics evidence linking gut microbiota alterations to sphingolipid and glycerophospholipid metabolic pathways.
Depression is a common and debilitating psychiatric disorder, and current pharmacotherapies are often limited by delayed onset, variable efficacy, and adverse side effects. Therefore, safer and more effective adjunctive or alternative strategies are needed. In the present study, a chronic unpredictable mild stress-induced murine model was used to evaluate the antidepressant potential of Lactiplantibacillus plantarum KLDS1.0344 by integrating behavioral assessments, neurochemical analyses, 16S rRNA sequencing, and untargeted metabolomics of intestinal contents. KLDS1.0344 significantly ameliorated depressive-like behaviors in the open field, tail suspension, forced swim, and sucrose preference tests, with the most pronounced effects observed at the high dose. These behavioral improvements were accompanied by reduced HPA-axis hormones (corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone) and partial restoration of monoamine neurotransmitters (dopamine, norepinephrine, and 5-hydroxytryptamine) and brain-derived neurotrophic factor. Multi-omics analyses further showed that high-dose KLDS1.0344 was associated with remodeling of the gut microbiota, particularly the restoration of Lactobacillus and alterations in other key taxa, together with marked changes in sphingolipid- and glycerophospholipid-related metabolic profiles. Correlation analysis suggested coordinated associations between microbial shifts and intestinal lipid metabolic features, supporting a candidate microbiota-metabolite framework related to the psychobiotic effects of KLDS1.0344. Overall, this study provides evidence supporting the psychobiotic potential of KLDS1.0344 and its possible application in functional foods for depression-related intervention.
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Effect of Hesperidin on Chronic Unpredictable Mild Stress-Related Depression in Rats through Gut-Brain Axis Pathway.
OBJECTIVES: To determine the pharmacological impact of hesperidin, the main component of Citri Reticulatae Pericarpium, on depressive behavior and elucidate the mechanism by which hesperidin treats depression, focusing on the gut-brain axis. METHODS: Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table, including control, model, hesperidin, probiotics, fluoxetine, and Citri Reticulatae Pericarpium groups. Except for the control group, rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT), immobility time in the forced swim test (FST), and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue, and the histopathology was performed to evaluate the changes of colon tissue, together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats. RESULTS: Compared to the control group, the rats in the model group showed notable reductions in body weight, SPF, and number in OFT (P<0.01). Hesperidin was found to ameliorate depression induced by CUMS, as seen by improvements in body weight, SPT, immobility time in FST, and number in OFT (P<0.05 or P<0.01). Regarding neurotransmitters, it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats (P<0.05). Compared to the control group, the colon tissue of the model group exhibited greater inflammatory cell infiltration, with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously, the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS, such as Shannon index increased and Simpson index decreased (P<0.01), while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group (P<0.05). CONCLUSION: The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.