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Microbiota-driven gut-brain signaling underlies antidepressant effects of a GLP-1 analog.
Despite widespread clinical use of glucagon-like peptide-1 receptor (GLP-1R) agonists for metabolic disease, their neuropsychiatric effects remain poorly understood and controversial. Here, we demonstrate that liraglutide alleviates depression through a gut-brain pathway that operates independently of GLP-1R. Using both pharmacological and genetic approaches, we demonstrated that liraglutide retained antidepressant efficacy in GLP-1R antagonist-Exn9-treated mice or in Glp1r-/- mice, whereas gut microbiota depletion abolished its effects. Multi-omics analyses revealed that liraglutide increased the abundance of Lactobacillus delbrueckii, which in turn restored the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG). The elevation of 2-AG mediated the antidepressant effects by normalizing excessive neuronal activity in emotional processing brain regions. Importantly, fecal microbiota transplantation from liraglutide-treated mice or Lactobacillus delbrueckii colonization replicated the antidepressant effects. These findings uncover a non-canonical mechanism of action for GLP-1 analogs, highlighting a specific microbiota-endocannabinoid metabolic pathway as a potential therapeutic target for depression.
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Mechanism of Microbiota-Gut-Brain in Perimenopausal Depression: An Inflammatory Perspective.
BACKGROUND: Perimenopausal women often experience physiological and psychological decline due to the effects of oestrogen fluctuations and the decline of ovarian function, leading to significantly increased depression rates, decreases in the quality of life and mental health issues. Studies have shown that the gut microbiota exerts anti-perimenopausal depression (PMD) effects via the microbiota-gut-brain (MGB) axis, the mechanisms of which may be related to inflammation. In this review, we discuss the effects and mechanisms of gut microbiota in PMD and provide new insights for future PMD treatment. METHODS: This review elaborates on the role of MGB axis in PMD from different aspects of inflammation, including gut microbiota metabolites, inflammatory signaling pathways, and clinical applications. RESULTS: Disorders of gut microbiota and decreased levels of gut microbiota metabolites (short-chain fatty acids, monoamine neurotransmitters) may cause PMD. The mechanism of intestinal microbiota-mediated inflammation may be related to TLR4/NF-κB pathway, NOD-like receptor protein 3 (NLRP3) inflammasome pathway and JAK-STAT pathway. At the same time, it was found that gut microbiota (probiotics, prebiotics, etc.) had good therapeutic potential in the treatment of PMD. CONCLUSIONS: MGB axis mediated inflammation may play an important role in PMD. The application of gut microbiota in the treatment of PMD patients has profound clinical transformation value, but a lot of efforts are still needed.
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Vagus nerve-dependent antidepressant effects of ineupatorolide B via gut microbiota modulation in a mouse model of depression.
Ineupatorolide B (InB), a sesquiterpene lactone with anti-inflammatory and anti-tumor properties, has not previously been evaluated for antidepressant effects. Given the central role of the gut-brain axis in stress-related mood disorders, we investigated whether InB alleviates depression-like phenotypes in mice exposed to chronic social defeat stress (CSDS) through microbiota- and vagus-dependent mechanisms. CSDS-susceptible mice received vehicle, fluoxetine, or InB and were assessed using behavioral paradigms, plasma inflammatory cytokine measurements, and analyses of synaptic-related protein expression in the medial prefrontal cortex (mPFC). CSDS induced robust depression-like behaviors, elevated interleukin-6 and tumor necrosis factor-α, caused splenomegaly, and reduced PSD-95 and BDNF expression in the mPFC. Repeated InB administration significantly reversed these behavioral, inflammatory, and synaptic abnormalities. 16S rRNA gene sequencing revealed that CSDS disrupted gut microbial α- and β-diversity, whereas InB treatment largely normalized these alterations and restored depression-associated short-chain fatty acids, including isobutyric and valeric acid, consistent with reestablishment of microbial metabolic homeostasis. Importantly, subdiaphragmatic vagotomy abolished the antidepressant-like, anti-inflammatory, and synaptic effects of InB, demonstrating that its efficacy requires intact vagus nerve-mediated gut-brain signaling. Together, these findings identify vagus-dependent modulation of the microbiota-immune-synaptic axis as a mechanistic pathway through which InB exerts antidepressant effects and highlight this compound as a potential microbiota-targeted therapeutic strategy for depression.
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Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve.
BACKGROUND: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion. METHODS: The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. RESULTS: The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. CONCLUSIONS: These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.
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Mechanism and therapeutic strategies of depression after myocardial infarction.
Depression resulted as an important factor associated with the myocardial infarction (MI) prognosis. Patients with MI also have a higher risk for developing depression. Although the issue of depression after MI has become a matter of clinical concern, the molecular mechanism underlying depression after MI remains unclear, whereby several strategies suggested have not got ideal effects, such as selective serotonin reuptake inhibitors. In this review, we summarized and discussed the occurrence mechanism of depression after MI, such as 5-hydroxytryptamine (5-HT) dysfunction, altered hypothalamus-pituitary-adrenal (HPA) axis function, gut microbiota imbalance, exosomal signal transduction, and inflammation. In addition, we offered a succinct overview of treatment, as well as some promising molecules especially from natural products for the treatment of depression after MI.
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Dihydromyricetin Alleviates Reserpine-Induced Depression by Modulating the Microbiota-Gut-Brain Axis.
Dihydromyricetin (DMY) is a natural flavonoid with neuroprotective and antidepressant potential, but its role in the microbiota-gut-brain axis remains unclear. Using a reserpine-induced depression rat model, we integrated behavioral, inflammatory, histological, microbiota, metabolomic, and fecal microbiota transplantation (FMT) analyses. DMY alleviated anhedonia, behavioral despair, and cognitive dysfunction, reduced circulating pro-inflammatory cytokines and hippocampal neuronal damage, and increased brain-derived neurotrophic factor expression. DMY also restored gut microbial diversity and composition and partially normalized bile acid and short-chain fatty acid profiles. Notably, FMT from DMY-treated donors reproduced antidepressant-like behavioral effects and restored key microbial metabolites. These findings suggest that DMY may alleviate depression-like phenotypes through coordinated regulation of gut microbiota, microbial metabolites, and neuroinflammatory responses, supporting its potential as a dietary strategy for depression management.
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MicroRNA signatures in neuroplasticity, neuroinflammation and neurotransmission in association with depression.
Depression is a multifactorial disorder that occurs mainly on account of the dysregulation of neuroplasticity, neurotransmission and neuroinflammation in the brain. In addition to environmental /lifestyle factors, the pathogenesis of disease has been associated with genetic and epigenetic factors that affect the reprogramming of normal brain function. MicroRNA (miRNAs), a type of non-coding RNAs, are emerging as significant players that play a vital role in the regulation of gene expression and have been extensively explored in neurodegenerative disorders. Recent studies have also shown the role of gut microbiota that forms a complex bidirectional network with gut brain axis, impacting neuroinflammation in case of Parkinson's disease and depression. Translating targeted miRNA-based therapies for the treatment of neurological disorders including depression, into clinical practice remains challenging due to the ineffective delivery of the therapeutic molecules and off-target effects of the specific miRNAs. This review provides significant insights into how miRNAs are emerging as vital players in the development of depression, especially the ones involved in three important processes including neuroplasticity, neurotransmission and neuroinflammation. In this review, the current status of miRNAs as biomarkers for therapeutic interventions in the case of depression has been discussed along with an overview of future perspectives, like use of nanotechnology and gene editing, keeping in view other multifactorial disorders where such interventions by mimics and inhibitors have already reached clinical trials. The challenges for targeting the specific miRNAs for therapeutic outcomes have also been highlighted.
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Absence of gut microbiota affects lipid metabolism in the prefrontal cortex of mice.
Objectives: Lipid metabolism is closely associated with many important biological functions. Here, we conducted this study to explore the effects of gut microbiota on the lipid metabolism in the prefrontal cortex of mice. Methods: Germ-free (GF) mice, specific pathogen-free (SPF) and colonized GF (CGF) mice were used in this study. The open field test (OFT), forced swimming test (FST) and novelty suppressed feeding test (NSFT) were conducted to assess the changes in general behavioral activity. The liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) was used to obtain the lipid metabolites. Both one-way analysis of variance (one-way ANOVA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to obtain the key differential lipid metabolites. Results: The behavioral tests showed that compared to SPF mice, GF mice had more center distance, more center time, less immobility time and less latency to familiar food. Meanwhile, 142 key differential lipid metabolites between SPF mice and GF mice were identified. These lipid metabolites mainly belonged to glycerophospholipids, glycerolipids, sphingolipids, and saccharolipids. The gut microbiota colonization did not reverse these changed behavioral phenotypes, but could restore 25 key differential lipid metabolites. Discussion: These results showed that the absence of gut microbiota could influence host behaviors and lipid metabolism. Our findings could provide original and valuable data for future studies to further investigate the microbiota-gut-brain axis.
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Levilactobacillus brevis SG031 modulates mood-related behaviors and attenuates stress-related sleep disturbance and autonomic dysfunction via gut microbiota modulation in Wistar-Kyoto rats.
AIMS: The probiotic bacterium Levilactobacillus brevis (L. brevis) has been proposed as a potential solution to manage mood disorders and alleviate stress-related sleep disturbances. However, the underlying mechanisms of its effects have not been fully elucidated. The aim of this study was to explore the impact and potential mechanisms of L. brevis SG031 supplementation on anxiety/depression-like behaviors and stress-induced changes in sleep patterns and sleep-related autonomic function. MAIN METHODS: Male Wistar-Kyoto rats were administered low, medium, or high doses of L. brevis SG031 or a vehicle for 4 weeks, followed by behavioral tests to evaluate anxiety and depression. After an additional 2 weeks of SG031 or vehicle administration, a cage-exchange paradigm was performed with 24-hour physiological signal measurements under different stress conditions. Fecal samples were collected to construct a 16S rRNA library and assess fecal short-chain fatty acids (SCFAs). KEY FINDINGS: High-dose SG031 administration yielded reduced depression-like responses and enhanced social interaction in behavioral tests. It also exhibited a protective effect against stress-induced sleep disturbance characterized by decreased sleep time, increased awake time, and autonomic dysfunction during sleep. Fecal examination indicated that high-dose SG031 administration exerted beneficial effects on gut health by maintaining the gut microbial abundance, preserving stability of the microbial composition, and enriching the gut with SCFAs, which were associated with improvements in sleep and autonomic function. SIGNIFICANCE: These findings collectively underscore the multifaceted potential of SG031 in addressing mental health and stress-related sleep challenges through the modulation of the gut microbiota.
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Study on the ameliorative effect of marine fungus Hansfordia sinuosae extracellular polysaccharide on DSS-induced ulcerative colitis and depression-like behavior.
Colitis has become a public health problem in recent years due to its high incidence rate. The extracellular polysaccharides produced by microorganisms were reported to possess the ability to alleviate colitis. A mannan (HPA) was isolated from the fermented broth of the marine fungus Hansfordia sinuosae, and its effect on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) was investigated in vivo. The results showed that HPA could relieve the disease symptoms and colon pathological injury of UC mice. Further mechanism analysis indicated that HPA repressed the level of NLRP3 inflammasome and inflammatory mediators TNF-α and IL-1β, and promoted the production of IL-10. HPA repaired the colonic barrier by increasing the expression of tight junction proteins ZO-1 and occludin, as well as the number of goblet cells. It also restored the imbalance of the gut microbiota caused by DSS treatment by enhancing the abundance of beneficial bacteria such as Clostridia UCG-014 and Bifidobacterium, while reducing the abundance of potentially harmful bacteria like Escherichia-Shigella and Enterococcus. Besides, HPA relieved the depression-like behavior of UC mice by inhibiting inflammatory response and activation of astrocyte and microglia in brain tissues. In short, HPA had the potential to be developed as functional foods or drugs for the treatment of colitis and accompanied depression-like behavior.