Deciphering the gut microbiota's (Coprococcus and Subdoligranulum) impact on depression: Network pharmacology and molecular dynamics simulation.

Depression, a prevalent mental health condition, significantly impacts global mental impairment rates. While antidepressants are commonly used, treatment-resistant depression (TRD) poses a challenge. Emerging research highlights the role of the gut microbiota in depression through the gut-brain axis. This study identifies key genes associated with depression influenced by specific gut microbiota, Coprococcus and Subdoligranulum. Using bioinformatics tools, potential targets were elucidated, and molecular docking studies were performed. Furthermore, gene expression analysis identified hub-genes related to depression, intersecting with metabolite targets. Protein-protein interaction analysis revealed pivotal targets such as PTGS2 and MMP9. Molecular docking demonstrated 3-Indolepropionic acid's superior affinity over (R)-3-(4-Hydroxyphenyl)lactate. Physicochemical properties and toxicity profiles were compared, suggesting favorable attributes for 3-Indolepropionic acid. Molecular dynamics simulations confirmed stability and interactions of compounds with target proteins. This comprehensive approach sheds light on the complex interplay between gut microbiota, genes, and depression, emphasizing the potential for microbiota-targeted interventions in mental health management.

Preclinical and clinical evidence of the association of colibactin-producing Escherichia coli with anxiety and depression in colon cancer.

BACKGROUND: The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent. The gut microbiota contributes to colorectal carcinogenesis (CRC), as demonstrated with colibactin-producing Escherichia coli (CoPEC). AIM: To evaluate the association between CoPEC prevalence and anxiety- and depressive-like behaviors with both preclinical and clinical approaches. METHODS: Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview. Results were compared according to the CoPEC colonization. In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain. Their behavior was assessed using the Elevated Plus Maze test, the Forced Swimming Test and the Behavior recognition system PhenoTyper®. RESULTS: In a limited cohort, all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis, whereas only one patient (17%) without CoPEC did. This result was confirmed in C57BL6/J wild-type mice and in a CRC susceptibility mouse model (adenomatous polyposis colimultiple intestinal neoplasia/+). Mice exhibited a significant increase in anxiety- and depressive-like behaviors after chronic infection with a CoPEC strain. CONCLUSION: This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties.

Human Gut Microbiota for Diagnosis and Treatment of Depression.

Nowadays, depressive disorder is spreading rapidly all over the world. Therefore, attention to the studies of the pathogenesis of the disease in order to find novel ways of early diagnosis and treatment is increasing among the scientific and medical communities. Special attention is drawn to a biomarker and therapeutic strategy through the microbiota-gut-brain axis. It is known that the symbiotic interactions between the gut microbes and the host can affect mental health. The review analyzes the mechanisms and ways of action of the gut microbiota on the pathophysiology of depression. The possibility of using knowledge about the taxonomic composition and metabolic profile of the microbiota of patients with depression to select gene compositions (metagenomic signature) as biomarkers of the disease is evaluated. The use of in silico technologies (machine learning) for the diagnosis of depression based on the biomarkers of the gut microbiota is given. Alternative approaches to the treatment of depression are being considered by balancing the microbial composition through dietary modifications and the use of additives, namely probiotics, postbiotics (including vesicles) and prebiotics as psychobiotics, and fecal transplantation. The bacterium Faecalibacterium prausnitzii is under consideration as a promising new-generation probiotic and auxiliary diagnostic biomarker of depression. The analysis conducted in this review may be useful for clinical practice and pharmacology.

A Narrative Review of Intestinal Microbiota's Impact on Migraine with Psychopathologies.

Migraine is a common and debilitating neurological disorder characterized by the recurrent attack of pulsating headaches typically localized on one side of the head associated with other disabling symptoms, such as nausea, increased sensitivity to light, sound and smell and mood changes. Various clinical factors, including the excessive use of migraine medication, inadequate acute treatment and stressful events, can contribute to the worsening of the condition, which may evolve to chronic migraine, that is, a headache present on >15 days/month for at least 3 months. Chronic migraine is frequently associated with various comorbidities, including anxiety and mood disorders, particularly depression, which complicate the prognosis, response to treatment and overall clinical outcomes. Emerging research indicates a connection between alterations in the composition of the gut microbiota and mental health conditions, particularly anxiety and depression, which are considered disorders of the gut-brain axis. This underscores the potential of modulating the gut microbiota as a new avenue for managing these conditions. In this context, it is interesting to investigate whether migraine, particularly in its chronic form, exhibits a dysbiosis profile similar to that observed in individuals with anxiety and depression. This could pave the way for interventions aimed at modulating the gut microbiota for treating difficult-to-manage migraines.

[Advances in the application of fecal microbiota transplantation for the treatment of nervous system diseases].

The intestinal microbiota exhibits a strong correlation with the function of the central nervous system, exerting influence on the host brain through neural pathways, immune pathways, and microbial metabolites along the gut-brain axis. Disorders in the composition of the intestinal microbial are closely associated with the onset and progression of neurological disorders, such as depression, Alzheimer's disease, and Parkinson's disease. It has been proven that fecal microbiota transplantation can improve symptoms in animal models of neurological diseases and clinical patients. This paper provides a comprehensive review of the composition and function of the human intestinal microbiota, as well as the intricate the relationship between the human intestinal microbiota and nervous system diseases through the gut-brain axis. Additionally, it delves into the research advancements and underlying mechanism of fecal microbiota transplantation in the treatment of nervous system diseases. These findings offer novel insights and potential avenues for clinical interventions targeting nervous system diseases.

Gut microbiota is necessary for pair-housing to protect against post-stroke depression in mice.

The goal of this study is to investigate the role of microbiota-gut-brain axis involved in the protective effect of pair-housing on post-stroke depression (PSD). PSD model was induced by occluding the middle cerebral artery (MCAO) plus restraint stress for four weeks. At three days after MCAO, the mice were restrained 2 h per day. For pair-housing (PH), each mouse was pair housed with a healthy isosexual cohabitor for four weeks. While in the other PH group, their drinking water was replaced with antibiotic water. On day 35 to day 40, anxiety- and depression-like behaviors (sucrose consumption, open field test, forced swim test, and tail-suspension test) were conducted. Results showed pair-housed mice had better performance on anxiety- and depression-like behaviors than the PSD mice, and the richness and diversity of intestinal flora were also improved. However, drinking antibiotic water reversed the effects of pair-housing. Furthermore, pair-housing had an obvious improvement in gut barrier disorder and inflammation caused by PSD. Particularly, they showed significant decreases in CD8 lymphocytes and mRNA levels of pro-inflammatory cytokines (TNF-a, IL-1ß and IL-6), while IL-10 mRNA was upregulated. In addition, pair-housing significantly reduced activated microglia and increased Nissl's body in the hippocampus of PSD mice. However, all these improvements were worse in the pair-housed mice administrated with antibiotic water. We conclude that pair-housing significantly improves PSD in association with enhanced functions of microbiota-gut-brain axis, and homeostasis of gut microbiota is indispensable for the protective effect of pair-housing on PSD.

The impact of depression-mediated gut microbiota composition on Irritable Bowel Syndrome: A Mendelian study.

OBJECTIVE: This study uses a two-sample Mendelian randomization (MR) analysis to delineate the causal influence of gut microbiota on the occurrence of irritable bowel syndrome (IBS), concurrently assessing the potential mediating function of depression within this framework. METHODS: Several two-sample MR methods were used to assess the causal repercussions of gut microbiota on the onset of both IBS and depression. Following this, gut microbiota and depression, which demonstrated notable causal associations, were integrated as exposure variables in a multivariable Mendelian randomization (MVMR) framework to construct a model encompassing gut microbiota, depression, and IBS. Mediation effects were assessed by examining the indirect pathway of gut microbiota → depression → IBS. RESULTS: Two-sample MR analysis unveiled a statistically significant causal association (P < 0.05) between specific bacterial group within the gut microbiota, notably p_Actinobacteria(OR = 0.829225), c_Clostridia(OR = 0.798897), s_Desulfovibrio_piger(OR = 1.163912), g_Streptococcus(OR = 1.132735), c_Actinobacteria(OR = 0.829224), and the onset of IBS. In the MVMR analysis, the relationship between depression and IBS was significant across Model 3, Model 7, Model 8, and Model 13 (P < 0.05). Assessment of mediation effects revealed that c_Clostridia and o_Clostridiales indirectly impacted IBS through depression, with masking effect ratios of 168.46 % and 168.44 %, respectively. CONCLUSION: These findings underscore a resilient causal association between the composition of gut microbiota and the initiation of IBS. Furthermore, depression serves as a mediator for particular groups of gut bacteria, thereby contributing to the development of IBS. These observations imply that interventions targeting mental health may potentially alleviate the risk of IBS onset attributable to adverse configurations of gut microbiota.

Oral microbiota dysbiosis alters chronic restraint stress-induced depression-like behaviors by modulating host metabolism.

Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression.

Exploring the Association between Anxiety, Depression, and Gut Microbiota during Pregnancy: Findings from a Pregnancy Cohort Study in Shijiazhuang, Hebei Province, China.

Negative emotions and gut microbiota during pregnancy both bear significant public health implications. However, the relationship between them has not been fully elucidated. This study, utilizing data from a pregnancy cohort, employed metagenomic sequencing to elucidate the relationship between anxiety, depression, and gut microbiota's diversity, composition, species, and functional pathways. Data from 87 subjects, spanning 225 time points across early, mid, and late pregnancy, were analyzed. The results revealed that anxiety and depression significantly corresponded to lower alpha diversity (including the Shannon entropy and the Simpson index). Anxiety and depression scores, along with categorical distinctions of anxiety/non-anxiety and depression/non-depression, were found to account for 0.723%, 0.731%, 0.651%, and 0.810% of the variance in gut-microbiota composition (p = 0.001), respectively. Increased anxiety was significantly positively associated with the abundance of Oscillibacter sp. KLE 1745, Oscillibacter sp. PEA192, Oscillibacter sp. KLE 1728, Oscillospiraceae bacterium VE202 24, and Treponema socranskii. A similar association was significantly noted for Oscillibacter sp. KLE 1745 with elevated depression scores. While EC.3.5.3.1: arginase appeared to be higher in the anxious group than in the non-anxious group, vitamin B12-related enzymes appeared to be lower in the depression group than in the non-depression group. The changes were found to be not statistically significant after post-multiple comparison adjustment.

Combined Effects of Early Life Stress and Prolonged Exposure to Western Diet on Emotional Responses and Gut Microbiota.

BACKGROUND: Exposure to early life stress (ELS) and maternal consumption of a high-fat and high-sugar diet can have detrimental effects on adult emotional responses. The microbiota and gut-brain axis have been proposed as playing a mediating role in the regulation of stress and emotion. METHOD: Young male rats were exposed to maternal separation (MS) together with maternal and postnatal consumption of a HFS diet (45%kcal saturated fat, 17%kcal sucrose). Anxiety-like behaviour was evaluated using an elevated zero-maze, and depression-like behaviour using the forced-swim and sucrose preference tests. Microbiota composition and derived metabolites were also analysed in faecal samples using a gas chromatograph and mass spectrometry. RESULTS: Combined exposure to MS and lifelong consumption of a HFS diet partially reversed the abnormal anxiety-like and depression-like behaviours in early adulthood caused by each adverse factor alone. Diet composition had a greater negative impact than ELS exposure on the gut microbiota, and both environmental factors interacted with microbiota composition partially counteracting their negative effects. CONCLUSIONS: The effects of exposure to early life stress and a HFS diet independently are partially reversed after the combination of both factors. These results suggest that ELS and diet interact to modulate adult stress response and gut microbiota.

A randomized, double-blinded, placebo-controlled clinical trial on Lactobacillus-containing cultured milk drink as adjuvant therapy for depression in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is frequently linked with coexisting mental illnesses. Our previous study discovered that 32.1% of IBS patients had subthreshold depression (SD), placing them at higher risk of developing major depression. Gut microbiota modulation through psychobiotics was found to influence depression via the gut-brain axis. However, the efficacy of lessening depression among IBS patients remains ambiguous. The study's aim was to investigate the roles of cultured milk drinks containing 109 cfu Lactobacillus acidophilus LA-5 and Lactobacillus paracasei L. CASEI-01 on depression and related variables among IBS participants with SD. A total of 110 IBS participants with normal mood (NM) and SD, were randomly assigned to one of four intervention groups: IBS-NM with placebo, IBS-NM with probiotic, IBS-SD with placebo, and IBS-SD with probiotic. Each participant was required to consume two bottles of cultured milk every day for a duration of 12 weeks. The following outcomes were assessed: depression risk, quality of life, the severity of IBS, and hormonal changes. The depression scores were significantly reduced in IBS-SD with probiotic and placebo from baseline (p < 0.001). Only IBS-SD with probiotic showed a significant rise in serotonin serum levels (p < 0.05). A significantly higher life quality measures were seen in IBS-SD with probiotic, IBS-SD with placebo, and IBS-NM with placebo (p < 0.05). All groups, both placebo and probiotic, reported significant improvement in IBS severity post-intervention with a higher prevalence of remission and mild IBS (p < 0.05). Dual strains lactobacillus-containing cultured milk drink via its regulation of relevant biomarkers, is a potential anti-depressive prophylactic agent for IBS patients at risk.

A microfluidic-based gut-on-a-chip model containing the gut microbiota of patients with depression reveals physiological characteristics similar to depression.

The diverse commensal microbiome of the human intestine has been considered to play a central role in depression. However, no host-microbiota co-culture system has been developed for depression, which hinders the controlled study of the interaction between depression and gut microbiota. We designed and manufactured a microfluidic-based gut-on-a-chip model containing the gut microbiota of patients with depression (depression-on-gut-chip, DoGC), which enables the extended co-culture of viable aerobic human intestinal epithelial cells and anaerobic gut microbiota, and allows the direct study of interactions between human gut microbiota and depression. We introduced representative gut microbiota from individuals with depression into our constructed DoGC model, successfully recapitulating the gut microbiota structure of depressed patients. This further led to the manifestation of physiological characteristics resembling depression, such as reduced gut barrier function, chronic low-grade inflammatory responses and decreased neurotransmitter 5-HT levels. Metabolome analysis of substances in the DoGC revealed a significant increase in lipopolysaccharides and tyrosine, while hyodeoxycholic acid, L-proline and L-threonine were significantly reduced, indicating the occurrence of depression. The proposed DoGC can serve as an effective platform for studying the gut microbiota of patients with depression, providing important cues for their roles in the pathology of this condition and acting as a powerful tool for personalized medicine.

Stress-induced mucin 13 reductions drive intestinal microbiome shifts and despair behaviors.

Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in microbiome composition are associated with disease pathology. Stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes in the context of stress. Using a model of chronic stress, we show that the glycocalyx protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a novel regulator of mucin 13 expression.

Unraveling the gut-brain connection: The association of microbiota-linked structural brain biomarkers with behavior and mental health.

AIM: The gut microbiota can influence human behavior. However, due to the massive multiple-testing problem, research into the relationship between microbiome ecosystems and the human brain faces drawbacks. This problem arises when attempting to correlate thousands of gut bacteria with thousands of brain voxels. METHODS: We performed brain magnetic resonance imaging (MRI) scans on 133 participants and applied machine-learning algorithms (Ridge regressions) combined with permutation tests. Using this approach, we were able to correlate specific gut bacterial families with brain MRI signals, circumventing the difficulties of massive multiple testing while considering sex, age, and body mass index as confounding factors. RESULTS: The relative abundance (RA) of the Selenomonadaceae, Clostridiaceae, and Veillonellaceae families in the gut was associated with altered cerebellar, visual, and frontal T2-mapping and diffusion tensor imaging measures. Conversely, decreased relative abundance of the Eubacteriaceae family was also linked to T2-mapping values in the cerebellum. Significantly, the brain regions associated with the gut microbiome were also correlated with depressive symptoms and attentional deficits. CONCLUSIONS: Our analytical strategy offers a promising approach for identifying potential brain biomarkers influenced by gut microbiota. By gathering a deeper understanding of the microbiota-brain connection, we can gain insights into the underlying mechanisms and potentially develop targeted interventions to mitigate the detrimental effects of dysbiosis on brain function and mental health.

Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3.

BACKGROUND: Remodeling eubiosis of the gut microenvironment may contribute to preventing the occurrence and development of depression. Mounting experimental evidence has shown that complement C3 signaling is associated with the pathogenesis of depression, and disruption of the gut microbiota may be an underlying cause of complement system activation. However, the mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown. RESULTS: In the present study, we found that chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well as cognitive impairment, which was associated with significant gut dysbiosis, especially enrichment of Proteobacteria and elevation of microbiota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation and central C3/CR3-mediated aberrant synaptic pruning in microglia have also been observed. Transplantation of gut microbiota from CUMS-induced depression model mice into specific pathogen-free and germ-free mice induced depression-like behavior and concomitant cognitive impairment in the recipient mice, accompanied by increased activation of the complement C3/CR3 pathway in the prefrontal cortex and abnormalities in microglia-mediated synaptic pruning. Conversely, antidepressants and fecal microbiota transplantation from antidepressant-treated donors improved depression-like behaviors and restored gut microbiome disturbances in depressed mice. Concurrently, inhibition of the complement C3/CR3 pathway, amelioration of abnormal microglia-mediated synaptic pruning, and increased expression of the synapsin and postsynaptic density protein 95 were observed. Collectively, our results revealed that gut dysbiosis induces the development of depression-like behaviors through abnormal synapse pruning in microglia-mediated by complement C3, and the inhibition of abnormal synaptic pruning is the key to targeting microbes to treat depression. CONCLUSIONS: Our findings provide novel insights into the involvement of complement C3/CR3 signaling and aberrant synaptic pruning of chemotactic microglia in gut-brain crosstalk in the pathogenesis of depression. Video Abstract.

Depression promotes breast cancer progression by regulating amino acid neurotransmitter metabolism and gut microbial disturbance.

INTRODUCTION: Breast cancer (BC) is the most prevalent type of cancer and has the highest mortality among women worldwide. BC patients have a high risk of depression, which has been recognized as an independent factor in the progression of BC. However, the potential mechanism has not been clearly demonstrated. METHODS: To explore the correlation and mechanism between depression and BC progression, we induced depression and tumor in BC mouse models. Depression was induced via chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS). Amino acid (AA) neurotransmitter-targeted metabonomics and gut microbiota 16S rDNA gene sequencing were employed in the mouse model after evaluation with behavioral tests and pathological analysis. RESULTS: The tumors in cancer-depression (CD) mice grew faster than those in cancer (CA) mice, and lung metastasis was observed in CD mice. Metabonomics revealed that the neurotransmitters and plasma AAs in CD mice were dysregulated, namely the tyrosine and tryptophan pathways and monoamine neurotransmitters in the brain. Gut microbiota analysis displayed an increased ratio of Firmicutes/Bacteroides. In detail, the abundance of f_Lachnospiraceae and s_Lachnospiraceae increased, whereas the abundance of o_Bacteroidales and s_Bacteroides_caecimuris decreased. Moreover, the gut microbiota was more closely associated with AA neurotransmitters than with plasma AA. CONCLUSION: Depression promoted the progression of BC by modulating the abundance of s_Lachnospiraceae and s_Bacteroides_caecimuris, which affected the metabolism of monoamine neurotransmitters in the brain and AA in the blood.

The role of vitamin D in depression and anxiety disorders: a review of the literature.

BACKGROUND: Prevalence of mental health disorders continue to increase worldwide. Over the past decades, suboptimal vitamin D (VD) levels and gut dysbiosis have been associated with neurological dysfunction and psychiatric disorders. METHODS: In this review, we examined the available literature on VD and mental health disorders, particularly depression and anxiety, in both clinical and pre-clinical studies. RESULTS: Our extensive review failed to find a link between VD deficiency, depression, and anxiety-related behavior in preclinical animal models. However, strong evidence suggests that VD supplementation may alleviate symptoms in chronically stressed rodents, with some promising evidence from clinical studies. Further, fecal microbiota transplantations suggest a potential role of gut microbiota in neuropsychiatric disorders, although the underlying mechanisms remain to be fully elucidated. It has been postulated that serotonin, primarily produced by gut bacteria, may be a crucial factor. Hence, whether VD has the ability to impact gut microbiota and modulate serotonin synthesis warrants further investigation. CONCLUSIONS: Taken together, literature has suggested that VD may serve as a key regulator in the gut-brain axis to modulate gut microbiota and alleviate symptoms of depression and anxiety. The inconsistent results of VD supplementation in clinical studies, particularly among VD deficient participants, suggests that current intake recommendations may need to be re-evaluated for individuals at-risk (i.e. prior to diagnosis) of developing depression and/or anxiety.

Astragaloside IV Alleviates Depression in Rats by Modulating Intestinal Microbiota, T-Immune Balance, and Metabolome.

This study aims to explore the effects of Astragaloside IV (AS-IV) on abnormal behaviors, intestinal microbiota, intestinal T-immune balance, and fecal metabolism of a model of depression in rats. Herein, we integrally applied 16S rRNA sequencing, molecular biological techniques, and 1H NMR-based fecal metabolomics to demonstrate the antidepression activity of AS-IV. The results suggested that AS-IV regulated the depression-like behaviors of rats, which are presented by an increase of body weight, upregulation of sucrose preference rates, and a decrease of immobility time. Additionally, AS-IV increased the abundances of beneficial bacteria (Lactobacillus and Oscillospira) in a model of depression in rats. Moreover, AS-IV regulated significantly the imbalance of Th17/Treg cells, and the abnormal contents of both anti-inflammatory factors and pro-inflammatory factors. Besides, fecal metabolomics showed that AS-IV improved the abnormal levels of short-chain fatty acids and amino acids. Collectively, our research supplemented new data, supporting the potential of AS-IV as an effective diet or diet composition to improve depression-like behaviors, dysfunctions of microbiota, imbalance of T immune, and the abnormality of fecal metabolome. However, the causality of the other actions was not proven because of the experimental design and the methodology used. The current findings suggest that AS-IV could function as a promising diet or diet composition to alleviate depressed symptoms.

Priming of microglia with dysfunctional gut microbiota impairs hippocampal neurogenesis and fosters stress vulnerability of mice.

BACKGROUND: Mental disorders may be involved in neuroinflammatory processes that are triggered by gut microbiota. How gut microbiota influence microglia-mediated sensitivity to stress remains unclear. Here we explored in an animal model of depression whether disruption of the gut microbiome primes hippocampal microglia, thereby impairing neurogenesis and sensitizing to stress. METHODS: Male C57BL/6J mice were exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, and effects on gut microbiota were assessed using 16S rRNA sequencing. Fecal microbiota was transplanted from control or CUMS mice into naïve animals. The depression-like behaviors of recipients were evaluated in a forced swimming test and sucrose preference test. The morphology and phenotype of microglia in the hippocampus of recipients were examined using immunohistochemistry, quantitative PCR, and enzyme-linked immunosorbent assays. The recipients were treated with lipopolysaccharide or chronic stress exposure, and effects were evaluated on behavior, microglial responses and hippocampal neurogenesis. Finally, we explored the ability of minocycline to reverse the effects of CUMS on hippocampal neurogenesis and stress sensitivity in recipients. RESULTS: CUMS altered the gut microbiome, leading to higher relative abundance of some bacteria (Helicobacter, Bacteroides, and Desulfovibrio) and lower relative abundance of some bacteria (Lactobacillus, Bifidobacterium, and Akkermansia). Fecal microbiota transplantation from CUMS mice to naïve animals induced microglial priming in the dentate gyrus of recipients. This microglia showed hyper-ramified morphology, and became more sensitive to LPS challenge or chronic stress, which characterized by more significant morphological changes and inflammatory responses, as well as impaired hippocampal neurogenesis and increased depressive-like behaviors. Giving minocycline to recipients reversed these effects of fecal transplantation. CONCLUSIONS: These findings suggest that gut microbiota from stressed animals can induce microglial priming in the dentate gyrus, which is associated with a hyper-immune response to stress and impaired hippocampal neurogenesis. Remodeling the gut microbiome or inhibiting microglial priming may be strategies to reduce sensitivity to stress.

Th17 cells sense microbiome to promote depressive-like behaviors.

BACKGROUND: Microbiome alterations have been associated with depression, and fecal transfer of depressed patients' microbiomes is sufficient to enhance despair behaviors in rodents. Yet little is known about the potential mechanisms, whereby microbes modulate depressive-like behaviors. RESULTS: In this study, we showed that certain bacteria known to induce Th17 cells are increased in depressed patients and mice exhibiting learned helplessness. Fecal transfers of human depressed patients' microbiomes into germ-free-like mice were sufficient to decrease sociability and increased susceptibility to the learned helplessness paradigm, confirming that the microbiome is sufficient to confer depressive-like behaviors. This microbial effect was dependent on the presence of Th17 cells in the recipient, as germ-free-like recipient mice deficient in Th17 cells were resistant to the behavioral changes induced by the microbiome of depressed patients. CONCLUSION: Altogether, these findings suggest a crucial role of the microbiome/Th17 cell axis in regulating depressive-like behaviors. Video Abstract.