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Repeated 3,3-Dimethyl-1-butanol exposure alters social dominance in adult mice.
The influence of gut microbiota on brain function and brain disorders has been attracted more and more attention. Trimethylamine N-oxide (TMAO), an indirect metabolite of gut microbiota, has been linked to aging, cognitive impairment, and other brain disorders. However, the relationship between TMAO and social behaviors are still poorly understood. Adult male mice were exposed to drinking water containing 3,3- Dimethyl-1-butanol (DMB), an indirect inhibitors of TMAO, for 21 continuous days followed by a series of behavioral tests to detect the effect of DMB exposure on social behaviors, mainly including social dominance test (SDT), bedding preference test (BP), sexual preference test (SP), social interaction test (SI), open field test (OFT), tail suspension test (TST), forced swim test (FST), novelty suppressed feeding test (NSF), and novel object recognition (NOR) task. In the SDT, compared with the control group, the mice treated with DMB (both 0.2% and 1.0%), both high-ranked and low-ranked mice, showed a reduction in the number of victories. There is no statistical difference on sexual preference, anxiety, depression-like behavior phenotype, and memory formation. In conclusion, the present findings provide direct evidence, for the first time, that repeated DMB exposure produces significant effects on social dominance of adult mice, without any effects on sexual preference, anxiety, depression-like behavior phenotype or memory formation, highlighting the regulatory effects of gut-brain interaction on social behaviors.
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Electroconvulsive therapy modulates brain plasticity in male depression: Links to gut microbial metabolites and diet-derived regulation of Wnt/BDNF signaling.
Electroconvulsive therapy (ECT) stands as the most effective intervention for treatment-resistant depression; however, its interaction with dietary regulation of the gut-brain axis has not been thoroughly explored. This study aimed to elucidate the mechanistic link between ECT, gut microbiota remodeling, short-chain fatty acid (SCFA) production, and neural plasticity. In this study, mice were subjected to chronic restraint stress (6 h/d for 28 consecutive days) to establish a depression-like model. Utilizing a translational approach that incorporated behavioral assessments, multimodal neuroimaging techniques such as PET-CT and laser speckle contrast imaging, along with multiomics analyses including metagenomics, metabolomics, and transcriptomics in rodent models, we demonstrated that ECT induced significant gut microbiota remodeling, characterized by an enrichment of SCFA-producing genera like Lactobacillus and Bifidobacterium. This remodeling was associated with restored intestinal barrier integrity and elevated plasma SCFA levels. Mechanistically, these microbial metabolites activated hippocampal Wnt/β-catenin signaling pathways, enhancing synaptic plasticity restoration, while concurrent probiotic supplementation further amplified brain-derived neurotrophic factor (BDNF) expression via SCFA-dependent epigenetic mechanisms. Neuroimaging corroborated the normalization of cerebral glucose metabolism and hemodynamic function post-ECT. In conclusion, our findings unveil a novel gut-brain communication pathway by which ECT exerts its antidepressant effects, positioning SCFAs as vital mediators connecting microbial metabolic alterations to neural plasticity. This research not only redefines the role of nutritional biochemistry in neuromodulation but also suggests the potential of microbial metabolite monitoring to tailor antidepressant therapies for enhanced efficacy.
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Changes in fecal microbiota composition and the cytokine expression profile in school-aged children with depression: A case-control study.
Depression in childhood negatively affects the growth and development, school performance, and peer or family relationships of affected children, and may even lead to suicide. Despite this, its etiology and pathophysiology remain largely unknown. Increasing evidence supports that gut microbiota plays a vital role in the development of childhood depression. However, little is known about the underlying mechanisms, as most clinical studies investigating the link between gut microbiota and depression have been undertaken in adult cohorts. In present study, a total of 140 school-aged children (6-12 years) were enrolled, including 92 with depression (male/female: 42/50) and 48 healthy controls (male/female: 22/26) from Lishui, Zhejiang, China. Illumina sequencing of the V3-V4 region of the 16S rRNA gene was used to investigate gut microbiota profiles while Bio-Plex Pro Human Cytokine 27-plex Panel was employed to explore host immune response. We found that, compared with healthy controls, children with depression had greater bacterial richness and altered β-diversity. Pro-inflammatory genera such as Streptococcus were enriched in the depression group, whereas anti-inflammatory genera such as Faecalibacterium were reduced, as determined by linear discriminant analysis effect size. These changes corresponded to altered bacterial functions, especially the production of immunomodulatory metabolites. We also identified the presence of a complex inflammatory condition in children with depression, characterized by increased levels of pro-inflammatory cytokines such as IL-17 and decreased levels of anti-inflammatory cytokines such as IFN-γ. Correlation analysis demonstrated that the differential cytokine abundance was closely linked to changes in gut microbiota of children with depression. In summary, key functional genera, such as Streptococcus and Faecalibacterium, alone or in combination, could serve as novel and powerful non-invasive biomarkers to distinguish between children with depression from healthy ones. This study was the first to demonstrate that, in Chinese children with depression, gut microbiota homeostasis is disrupted, concomitant with the activation of a complex pro-inflammatory response. These findings suggest that gut microbiota might play an important role in the pathogenesis of depression in school-aged children, while key functional bacteria in gut may serve as novel targets for non-invasive diagnosis and patient-tailored early precise intervention in children with depression.
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Alterations in Gut Microbiome Composition and Increased Inflammatory Markers in Post-COVID-19 Individuals.
Dysfunctions in the immune system and alterations in the microbiome composition following SARS-CoV-2 infection contribute to persistent neurological issues observed in long COVID-19 survivors. We hypothesize that alterations in the gut microbiome composition and peripheral inflammatory profile following COVID-19 may play pivotal roles in behavior changes among individuals experiencing long-term illness. This cross-sectional study included a sample of post-COVID-19 and non-COVID-19 subjects. We assessed the presence of psychiatric conditions utilizing standardized diagnostic criteria, Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression (HAM-D), Biological Rhythms in Neuropsychiatry Assessment Interview (BRIAN), and Functional Assessment Short Test (FAST). Plasma samples were analyzed to examine lipid and inflammatory profiles. Fecal samples were evaluated by 16S rRNA sequencing to identify the gut microbiome composition. Noteworthy findings include a significant increase in the myeloid progenitor inhibitory factor 1 (MPIF-1), interleukin (IL)-17, and triglyceride among post-COVID-19 individuals. While α-diversity in the gut microbiome composition showed no significant differences, β-diversity demonstrated a notable distinction between the healthy control and post-COVID-19 groups. Post-COVID-19 individuals exhibited a decreased abundance of phylum, class, and order of Verrucomicrobia, family, and genus of Akkermansia, a short-chain fatty acid producer and microbial group significantly associated with intestinal barrier homeostasis and the amelioration of metabolic diseases. No difference was found between the behavioral and clinical data. In post-COVID-19 individuals, there were elevated IL-17 and MPIF-1 levels, compared to non-COVID-19 individuals. Additionally, there were notable alterations in gut microbiome composition, as evidenced by changes in β-diversity and a decrease of Verrucomicrobia, family, and Akkermansia genus abundance.
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Lactococcus lactis and Bifidobacterium longum attenuate Clostridioides difficile- or Clostridium symbiosum-induced colitis and depression/anxiety-like behavior in male mice.
Clostridioides difficile causes severe colitis, which induces neuroinflammation and psychiatric disorder. In a preliminary study, we isolated Clostridium symbiosum from the stools of patients with ulcerative colitis. Therefore, we first examined whether oral infection with C. difficile or C. symbiosum could induce colitis and depression in male mice. Orally gavaged C. difficile or C. symbiosum caused diarrhea, bodyweight loss, depression/anxiety-like behavior, and tumor necrosis factor (TNF)-α and interleukin (IL)-6 overexpression in the colon and hippocampus in the pseudo-germ-free (PGF) and specific germ-free (SPF) mice. However, healthy volunteer microbiota-derived Lactococcus lactis P22 and/or Bifidobacterium longum P26 suppressed C. difficile or C. symbiosum growth and TNF-α expression in macrophage cells. They alleviated C. difficile- or C. symbiosum-induced bodyweight loss, diarrhea, and neurobehavioral changes in PGF and SPF mice, while reducing pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) levels in the colon and in the hippocampus. These findings suggest that C. difficile or C. symbiosum can cause colitis and depression/anxiety. Oral administration of P22 and/or P26 may alleviate gut bacteria-induced gut inflammation and depression/anxiety through the inhibition of their growth and inflammatory response.
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A novel anti-depression strategy utilizing γ-CD-MOFs delivery system for volatile oil from Alpiniae Oxyphyllae fructus - examining the mechanism of gut microbiota and neuroinflammation.
The volatile oil extracted from Alpiniae Oxyphyllae Fructus (AOVO) exhibits excellent anti-inflammatory properties but is unstable. Therefore, this study aimed to develop a cyclodextrin-based drug delivery system employing γ-cyclodextrin metal-organic frameworks (γ-CD-MOFs) to encapsulate AOVO, and examine its potential antidepressant mechanisms by integrating multi-omics approaches. The AOVO/γ-CD-MOFs system exhibited a well-ordered crystalline structure. Physicochemical analyses confirmed the successful encapsulation of AOVO within the γ-CD-MOFs matrix. This encapsulation enhanced the stability, solubility, and cumulative release rate of AOVO, augmenting its biosafety, and antidepressant effects of AOVO in vivo. Based on the predicted antidepressant mechanisms of the identified components of AOVO in vivo, the current study confirmed that the formulation improved the integrity of the intestinal barrier and reduced the level of pro-inflammatory cytokines, which were positively associated with the increased abundance of Ligilactobacillus. This shift helped in antagonizing the cascade of responses associated with neuroinflammation triggered by the peripheral inflammatory stimulation. Meanwhile, AOVO/γ-CD-MOFs prolonged fluorescence signals in brain and alleviated neuroinflammation, thereby exerting an antidepressant effect. Overall, this study developed a promising food-grade strategy for encapsulating and stabilizing volatile oil therapeutic agents, and proposed a new scheme for treating depression using the fabricated AOVO/γ-CD-MOFs system. These findings provide a preclinical proof-of-concept for using food-grade γ-CD-MOFs to stabilize volatile oil therapeutic agents and improve their delivery performance.
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Electro-acupuncture inhibits HDAC2 via modulating gut microbiota to ameliorate SNI-induced pain and depression-like behavior in rats.
BACKGROUND: Depression and chronic pain frequent co-occur, exacerbating each other's symptoms and hindering treatment. Emerging studies have highlighted abnormal gut microbiota in both conditions. Previous studies have demonstrated the clinical effectiveness of electro-acupuncture (EA) in managing these conditions, yet the underlying mechanisms remain elusive. METHODS: Spared nerve injury (SNI) was employed to induce chronic pain and depression-like behavior. Rats were randomly assigned to sham SNI (SS), SNI, and EA groups. SNI surgery was performed on all rats, except those in SS group, which underwent sham SNI surgery. Then EA group received 5 weeks of EA treatment. Pain and depression-like behavior were assessed through paw withdrawal threshold, sucrose-preference test, and forced swim test. Gut microbiota composition was analyzed via 16S rDNA sequencing. Brain-Derived Neurotrophic Factor (BDNF) and acetylation-related proteins in the medial prefrontal cortex (mPFC) were evaluated through enzyme-linked immunosorbent assay and western blot. RESULTS: EA treatment significantly ameliorated pain and depression-like behavior. The 16S rDNA sequencing showed EA modulated gut microbiota composition, increased short-chain fatty acids (SCFAs)-producing bacteria, including Akkermansi, Ruminococcaceae and Lachnospiraceae family, particularly Akkermansia. Furthermore, EA increased BDNF, AcH3 and decreased HDAC2 in mPFC. Notably, SCFAs-producing bacteria exhibited a negative correlation with HDAC2 levels. LIMITATIONS: This study exclusively investigated microbiota differences resulting from EA stimulation, without delving into the functional variations brought about by these microbial distinctions. CONCLUSIONS: The therapeutic effects of EA on the comorbidity of chronic pain and depression may involve the modulation of the gut microbiota, resulting in histone acetylation changes and upregulation of BDNF.
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Microalgae-Based Hydrogel for Inflammatory Bowel Disease and Its Associated Anxiety and Depression.
Patients diagnosed with inflammatory bowel disease (IBD) exhibit a notable prevalence of psychiatric disorders, such as anxiety and depression. Nevertheless, the etiology of psychiatric disorders associated with IBD remains uncertain, and an efficacious treatment approach has yet to be established. Herein, an oral hydrogel strategy (SP@Rh-gel) is proposed for co-delivery of Spirulina platensis and rhein to treat IBD and IBD-associated anxiety and depression by modulating the microbiota-gut-brain axis. SP@Rh-gel improves the solubility, release characteristics and intestinal retention capacity of the drug, leading to a significant improvement in the oral therapeutic efficacy. Oral administration of SP@Rh-gel can reduce intestinal inflammation and rebalance the disrupted intestinal microbial community. Furthermore, SP@Rh-gel maintains intestinal barrier integrity and reduces the release of pro-inflammatory factors and their entry into the hippocampus through the blood-brain barrier, thereby inhibiting neuroinflammation and maintaining neuroplasticity. SP@Rh-gel significantly alleviates the colitis symptoms, as well as anxiety- and depression-like behaviors, in a chronic colitis mouse model. This study demonstrates the significant involvement of the microbiota-gut-brain axis in the development of IBD with psychiatric disorders and proposes a safe, simple, and highly efficient therapeutic approach for managing IBD and comorbid psychiatric disorders.
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Honeysuckle-derived nanovesicles alleviate inflammatory bowel disease-associated neuropsychiatric disorders via the gut-brain axis.
RATIONALE: Inflammatory bowel disease (IBD) is frequently accompanied by anxiety and depression, yet effective therapies targeting both intestinal inflammation and neuropsychiatric symptoms remain limited. This study aimed to investigate whether honeysuckle-derived nanovesicles (HNVs) could alleviate IBD-related affective disturbances by modulating the microbial-gut-brain axis (MGBA). METHODS: A chronic colitis mouse model was established using dextran sulfate sodium (DSS). Mice were treated orally with HNVs, and anxiety- and depression-like behaviors were evaluated using behavioral assays. Intestinal barrier integrity, gut microbiota composition, systemic immune responses, proinflammatory cytokine production, hippocampal immune infiltration, 5-hydroxytryptamine (5-HT) biosynthesis and metabolism, and activation of the BDNF/TrkB/GSK3β signaling pathway were assessed using histological, microbiological, immunological, biochemical, and molecular analyses. RESULTS: Oral administration of HNVs markedly attenuated anxiety- and depression-like behaviors in mice with chronic colitis. HNV treatment preserved intestinal barrier integrity, reshaped the gut microbial community, modulated systemic immune responses, reduced proinflammatory cytokine production and hippocampal inflammatory infiltration, and regulated 5-HT biosynthesis and metabolic pathways. These effects were associated with restoration of intestinal and neural homeostasis and activation of the BDNF/TrkB/GSK3β signaling cascade. CONCLUSIONS: HNVs alleviated IBD-related affective disturbances in experimental chronic colitis by regulating the MGBA, suppressing inflammation, modulating 5-HT metabolism, and restoring intestinal and neural homeostasis. These findings support HNVs as a potential natural nanotherapeutic strategy for the integrated management of intestinal inflammation and associated neuropsychiatric comorbidities.
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Effect of Probiotics on Psychiatric Symptoms and Central Nervous System Functions in Human Health and Disease: A Systematic Review and Meta-Analysis.
BACKGROUND: The gut microbiota impacts on central nervous system (CNS) function via the microbiota-gut-brain axis. Thus, therapeutics targeting the gut microbiota such as probiotics have the potential for improving mental health. This meta-analysis synthesizes the evidence regarding the impacts of probiotics on psychological well-being, psychiatric symptoms and CNS functioning. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were applied for executing this review using the databases PubMed, Web of Science and Cochrane Library. The data were summarized at qualitative and quantitative level. RESULTS: Fifty-four randomized placebo-controlled studies were included, of which 30 were eligible for meta-analysis. If investigated, the probiotics mostly exerted effects on CNS function. Most probiotics did not affect mood, stress, anxiety, depression and psychiatric distress when compared to placebo at the qualitative level. At quantitative level, depression and psychiatric distress improved slightly in the probiotic condition (depression: mean difference -0.37 (95% CI: -0.55, -0.20); p ≤ 0.0001; psychiatric distress: mean difference -0.33 (95% CI: -0.53, -0.13); p = 0.001). CONCLUSIONS: To date it is unclear to which extent and in which specific areas next generation probiotics selected and developed for their ability to improve psychiatric condition and potentially other CNS functions are promising.