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[What is the role of the gut microbiota in the development of alcohol use disorders?].
Alcohol addiction is a complex and multifactorial disease influenced by social, psychological and biological aspects. The current pharmacological drugs used in the management of alcohol dependence have shown only a modest efficacy and the relapse rate remains high in this disease. Recently, the gut microbiota, a huge and dynamic ecosystem made up of billions of microorganisms living in our intestine, has been shown to regulate many important functions for human health. Indeed, the gut microbiota is known to influence our metabolism, our immune system as well as our nervous system with consequences for brain functions, mood and behaviour. We have shown that heavy and chronic alcohol consumption induced important changes in the composition of the gut microbiota. Furthermore, the microbial changes are associated with the severity of depression, anxiety and alcohol craving that are important factors predicting the risk of relapse. This suggests the existence of a gut-brain axis in alcohol dependence and supports the development of new therapeutic alternatives, targeting the gut microbiota, in the management of alcohol dependence.
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Gut microbiota and late-life depression: from mechanistic insights to clinical rehabilitation.
Emerging evidence identifies the gut microbiota as a promising therapeutic target for late-life depression, yet its mechanisms and clinical applications remain insufficiently defined in aging populations. This review synthesizes findings from animal studies and clinical trials to examine how the gut microbiota contributes to late-life depression and to evaluate potential intervention. We first outline the association between microbial ecosystem alterations and mental health, emphasizing their relevance for late-life depression. Mechanistic pathways are then discussed in sequence: disruption of intestinal microbial networks that impair barrier integrity, dysregulation of microbial metabolites that disturb gut-brain communication, and maladaptive immune activation and signal transduction at the host-microbe interface. Building on these insights, we assess the therapeutic approaches, including dietary interventions, probiotics, prebiotics, postbiotics, and fecal microbiota transplantation. Recovery outcomes are also summarized, covering microbial composition, metabolite changes, neurological biomarkers and neuroimaging findings. Finally, we address major translational challenges, including individual variability, dynamic monitoring, technological limitations, and safety concerns. We highlight the methodological gaps that limit current research and propose future directions to advance mechanistic understanding and clinical translation. By integrating ecological balance with personalized strategies, gut microbiota-based interventions hold potential to improve prevention and treatment of late-life depression.
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Butyric acid and valeric acid attenuate stress-induced ferroptosis and depressive-like behaviors by suppressing hippocampal neuroinflammation.
BACKGROUND: Depression is closely associated with stress-induced hippocampal damage and dysfunction. Emerging evidence demonstrates that the gut microbiota and its metabolites, acting as probiotics or prebiotics, can modulate brain structure and function via the gut-brain axis, thereby offering therapeutic potential for ameliorating related neurological and psychiatric disorders. This study delves into the contribution of the gut microbiota and its metabolites to stress-induced ferroptosis of hippocampal neurons and the associated molecular pathways. METHODS: This study used time-course stress paradigms combined with ferroptosis inhibitors to identify hippocampal neuronal ferroptosis. Fecal microbiota transplantation were conducted to analyze the role of gut microbiota in this process. Subsequently, 16 S rDNA sequencing and metabolomics techniques were applied to identify key gut microbiota and metabolites. Metabolites intervention were performed to examine their causal relationship with neuronal ferroptosis. Finally, we used histochemical and molecular assays to assess both intestinal and blood-brain barrier integrity as well as inflammation in peripheral blood and hippocampal tissue, along with GPR41/RhoA/Rock1 pathway changes, to preliminarily investigate the molecular mechanisms underlying stress-induced hippocampal neuronal ferroptosis. RESULTS: We demonstrated that stress triggered hippocampal neuronal ferroptosis and subsequent depressive-like behaviors in mice. Fecal microbiota transplantation successfully replicated the ferroptosis phenotype. Butyric acid and valeric acid were identified as key metabolites significantly reduced in the serum of acutely and chronically stressed mice, respectively. Intervention with these metabolites markedly alleviated ferroptosis. Furthermore, valerate intervention increased hippocampal GPR41 expression and significantly suppressed the pro-inflammatory RhoA/Rock1 pathway in chronically stressed mice, thereby reducing neuroinflammation and ameliorating neuronal ferroptosis. However, butyrate intervention showed no significant effect on the GPR41/RhoA/Rock1 pathway. CONCLUSION: Stress induces ferroptosis in hippocampal neurons, where reduced abundance of short-chain fatty acid-producing bacteria plays a key role. Key metabolites butyric acid and valeric acid alleviate neuroinflammation to improve ferroptosis via the gut-brain axis in acute and chronic stress, respectively. Specifically, valeric acid exerts neuroprotective effect through the GPR41/RhoA/Rock1 pathway, whereas butyric acid-mediated protection likely operates through alternative mechanisms.
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6'-Sialyllactose Combined with Bifidobacterium animalis subsp. lactis BB12 Relieves Constipation and Depression-like Behaviors Induced by Loperamide in Mice by Regulating the Gut-Brain Axis.
Constipation is a common gastrointestinal disorder, which impairs health and quality of life. This study evaluated the ameliorating effects and underlying mechanism of 6'-sialyllactose (6'-SL) and Bifidobacterium animalis subsp. lactis BB12 (BB12) on loperamide-induced constipation and associated depression-like behaviors. 6'-SL combined with BB12 increased the fecal water content, fecal pellet number, and gastrointestinal transit rate while reducing the time of first black feces. 6'-SL and BB12 modulated secretion of intestinal neurotransmitters, regulated expression of AQP3 and Claudin-1, and modulated expression of key proteins in the SCF/c-Kit pathway. Meanwhile, 6'-SL and BB12 ameliorated depression-like behaviors by inhibiting inflammatory responses and modulating the expression of synaptic plasticity-related proteins in the brain. Moreover, 6'-SL and BB12 regulated the diversity of gut microbiota, enhanced the relative abundance of Bacteroidetes and Akkermansia, and elevated SCFA levels. This study provides a theoretical and practical basis for developing functional foods based on synbiotics containing 6'-SL and BB12.
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Xuefu Zhuyu Capsule alleviates depression in post-stroke depression model rats via modulation of the gut microbiota-gut-brain axis.
Xuefu Zhuyu Capsule (XFZY) demonstrated potential in alleviating post-stroke depression (PSD), a condition whose underlying mechanisms may involve the gut-brain axis. This study aimed to explore the therapeutic effects of XFZY on PSD and its possible modulation of the gut microbiota-gut-brain axis in a rat model. Wistar rats were randomly assigned to sham, PSD, three XFZY dose (0.216, 0.432, 0.864 g/kg), and fluoxetine (1.80 mg/kg) groups (n = 12 per group). The PSD model was established using transient middle cerebral artery occlusion (t-MCAO) combined with chronic unpredictable mild stress (CUMS), followed by 28 days of XFZY administration. In a separate experiment, gut microbiota was depleted via antibiotic cocktails, with rats divided into sham, PSD, XFZY medium Dose (XFM), pseudo-germ-free (PGF) and PGF + XFM (PGFX) groups. Behavioral tests indicated that XFZY ameliorated depressive-like behaviors, with the medium dose (0.432 g/kg) showing the most significant effect. Histological analysis using hematoxylin and eosin (H&E) and Nissl staining revealed that XFZY alleviated colonic and neuronal damage. Furthermore, 16S rRNA sequencing and gas chromatography revealed that XFZY modulated gut microbiota composition, increased species richness, and elevated levels of short-chain fatty acids such as acetic acid, propionic acid, and butyric acid. Enzyme-Linked Immunosorbent Assay (ELISA) results showed that XFZY reduced pro-inflammatory cytokines - interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), while immunohistochemistry indicated enhanced intestinal barrier function and reduced neuroinflammation. Furthermore, after depletion of gut microbiota using antibiotic cocktails, these therapeutic effects of XFZY were abolished. In summary, XFZY may alleviate PSD by modulating the gut microbiota and regulating the gut-brain axis, offering a promising direction for future therapeutic research.
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Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain.
Emerging evidence suggests that the gut microbiota may interact with the host brain and play pivotal roles in the pathogenesis of neuropsychiatric disorders. However, the mechanism underlying reciprocal interactions along the microbiota-gut-brain axis in depression remains unclear. In this study, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression. The results showed that CRS mice displayed depression- and anxiety-like behaviors. Additionally, kynurenine (Kyn) and its metabolites, an important Trp metabolic pathway, were strongly activated in the brain. Intriguingly, the Kyn toxic signaling was exacerbated in the gut, especially in the colon. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme responsible for Kyn metabolic pathway initiation, was significantly upregulated in the brain and gut in CRS mice compared with control mice, promoting transfer of Trp metabolic pathway to Kyn signaling. Additionally, administration of IDO inhibitor, 1-methyl-tryptophan (1-MT), partially rescued CRS-induced depression- and anxiety-like changes. Moreover, the enhanced intestinal permeability mediated by CRS allowed toxic metabolites to "leak" into the bloodstream. The microbiome profiles of CRS mice displayed obviously altered taxonomic composition and negative correlations were observed between Enterorhabdus, Parabacteroides and Kyn levels in the brain. Reciprocal crosstalk between the brain and gut was further validated by citalopram treatment, IDO inhibitor and microbiota intervention, which counteracted depression-like behavior, Kyn metabolic signaling and microbiota composition in CRS mice. Meanwhile, Parabacteroides treatment affected Trp metabolism in mouse hippocampus, manifesting as elevated concentration of 5-HT as well as ratio of 5-HT to Trp. These results suggest that long-term stress disrupts Kyn metabolism and endocrine function along the gut-brain axis, accompanied by the disrupted homeostasis of certain microbiota, which collectively contribute to the development of depression-like behavior.
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Ingestion of Faecalibaculum rodentium causes depression-like phenotypes in resilient Ephx2 knock-out mice: A role of brain-gut-microbiota axis via the subdiaphragmatic vagus nerve.
BACKGROUND: The brain-gut-microbiota axis plays a crucial role in the bidirectional interactions between the brain and the gut. Soluble epoxide hydrolase (coded by the Ephx2 gene) plays an important role in inflammation, which has been implicated in stress-related depression. Ephx2 knock-out (KO) mice exposed to chronic social defeat stress (CSDS) did not show depression-like behaviors, indicating stress resilience. Here we examined whether the brain-gut-microbiota axis influences the resilience in Ephx2 KO mice. METHODS: Effects of fecal microbiota transplantation (FMT) from CSDS-susceptible (or control) mice in wild-type (WT) mice and Ephx2 KO mice treated with an antibiotic cocktail (ABX) were investigated. Behavioral, biochemical tests and 16S ribosome RNA analysis were performed. RESULTS: FMT from CSDS-susceptible mice produced anhedonia-like behavior in ABX-treated WT and Ephx2 KO mice. The 16S ribosome RNA analysis showed that Faecalibaculum rodentium (F. rodentium) may be responsible for the observed anhedonia-like behavior following FMT from CSDS-susceptible mice. Ingestion of F. rodentium for 14 days produced depression- and anhedonia-like behaviors, higher blood levels of interleukin-6, and reduced expression of synaptic proteins in the prefrontal cortex of ABX-treated Ephx2 KO mice. Furthermore, subdiaphragmatic vagotomy blocked the development of these behavioral abnormalities after ingestion of F. rodentium. LIMITATIONS: Detailed mechanisms are unclear. CONCLUSIONS: These findings suggest that F. rodentium might contribute to the conversion of resilient Ephx2 KO mice into KO mice with depression-like phenotypes. The brain-gut-microbiota axis via the subdiaphragmatic vagus nerve plays a crucial role in susceptibility and resilience to stress.
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Dietary Fatty Acids and Microbiota-Brain Communication in Neuropsychiatric Diseases.
The gut-brain axis is a multimodal communication system along which immune, metabolic, autonomic, endocrine and enteric nervous signals can shape host physiology and determine liability, development and progression of a vast number of human diseases. Here, we broadly discussed the current knowledge about the either beneficial or deleterious impact of dietary fatty acids on microbiota-brain communication (MBC), and the multiple mechanisms by which different types of lipids can modify gut microbial ecosystem and contribute to the pathophysiology of major neuropsychiatric diseases (NPDs), such as schizophrenia (SCZ), depression and autism spectrum disorders (ASD).
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Gut Microbiota: A Pivotal Hub for Polyphenols as Antidepressants.
Polyphenols, present in a broad range of plants, have been thought to be responsible for many beneficial health effects, such as an antidepressant. Despite that polyphenols can be absorbed in the small intestine directly, most of them have low bioavailability and reach the large intestine without any modifications due to their complex structures. The interaction between microbial communities and polyphenols in the intestine is important for the latter to exert antidepressant effects. Gut microbiota can improve the bioavailability of polyphenols; in turn, polyphenols can maintain the intestinal barrier as well as the community of the gut microbiota in normal status. Furthermore, gut microbita catabolize polyphenols to more active, better-absorbed metabolites, further ameliorating depression through the microbial-gut-brain (MGB) axis. Based on this evidence, the review illustrates the potential role of gut microbiota in the processes of polyphenols or their metabolites acting as antidepressants and further envisions the gut microbiota as therapeutic targets for depression.
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Genetically supported causality between gut microbiota, prefrontal cortex and depression: insights from multiple Mendelian randomization, multi-omics analysis, and network pharmacology.
BACKGROUND: Gut microbiota (GM) alterations have been implicated in depression, potentially mediated via changes in the prefrontal cortex (PFC). However, the causal relationship and underlying biological mechanisms remain unclear. METHODS: Summary statistics from genome-wide association studies (GWAS) of 473 GM (n = 5959), depression (43,280 cases, 329,192 controls), and 3935 brain imaging-derived phenotypes (IDPs) (n = 33,224) were utilized. Univariable Mendelian randomization (MR) analyses examined the associations between (i) GM and depression, (ii) depression and GM, (iii) brain IDPs and depression, and (iv) GM and PFC-related IDPs. Multivariable MR (MVMR) assessed whether PFC structural phenotypes mediated the effect of GM on depression risk. Summary-data-based MR (SMR) identified potential genes and therapeutic targets. Single-cell RNA sequencing and bulk RNA data from GEO database about PFC tissue of depression patients were analyzed for biomarker expression and regulatory mechanisms. Target genes were validated in mice model through behavioral tests, RT-qPCR, and immunofluorescence analyses. Drug prediction and molecular docking explored potential therapeutic targets and traditional Chinese medicine. RESULTS: The analysis identified 15 positive and 16 negative causal effects between GM and depression. Reverse MR analysis revealed 36 GM traits with reverse causality to depression. After excluding results with heterogeneity and pleiotropy, 11 PFC-related IDPs exhibited causal relationships with depression. MVMR adjustment for genetically predicted GM levels showed that the effects of PFC-related IDPs remained significant, indicating mediation of GM's effect on depression. Integration of GWAS and eQTL data identified 14 genes passing the SMR test. Differential expression of these genes was observed across cell types and between patients with depression and healthy controls. FARS2 and SLC25A21 were identified as potential therapeutic targets for depression, with protective effects shown in MR analysis (FARS2: OR: 0.892, 95 % CI: 0.813-0.971, P = 0.005; SLC25A21: OR: 0.924, 95 % CI: 0.851-0.997, P = 0.035). Reduced expression of FARS2 and SLC25A21 was validated in CUMS induced mice, along with depressive-like behaviors confirmed through behavioral tests. Molecular docking predicted Betanidin, Aloenin B, Rehmannioside D, and Vicenin-2 as potential drugs targeting both FARS2 and SLC25A21. CONCLUSION: This study supports causal relationships between specific GM and depression, with PFC structures potentially mediating these effects. The findings provide insights into personalized depression treatment strategies and identify promising candidate targets and drugs for future research.