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Cell-Type-Specific WTAP and ALKBH5-Mediated m6A Methylation Orchestrates Mental Disorders via Gut-Brain Axis Metabolite Signaling: Multi-Omics Evidence and Pyroptosis-Associated Loop Mechanism.
INTRODUCTION: Mental disorders affect one billion people and contribute 5% of global DALYs. Although N6-methyladenosine (m6A) modification, gut microbiota, cerebrospinal fluid (CSF) metabolites, and pyroptosis have been implicated in disease pathogenesis, the directionality and magnitude of causal links remain elusive. We integrated two-sample Mendelian randomization (MR) with single-cell eQTL data to generate hypotheses regarding these relationships. METHODS: Using large-scale GWAS summary statistics, we estimated the causal effects of m6A regulators, gut microbiota, CSF metabolites, and pyroptosis on depression, schizophrenia (SZ), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD). Mediation analysis quantified hypothesized microbiota- and metabolite-mediated proportions; single-cell eQTL from 14 immune subsets localized genetic associations to cell types. RESULTS: MR analysis suggested distinct causal associations of m6A modifiers (WTAP/ALKBH5) with mental disorders. Gut microbiota (e.g., GCA-900066755, Bacillus) and CSF metabolites (e.g., theophylline, isoleucine) were estimated to potentially mediate 5.06%-45.28% of these effects, forming pathways such as WTAP → GCA-900066755 → theophylline → ADHD and ALKBH5 → CAG-390 → isoleucine → PTSD. These represent statistically inferred associations rather than experimentally validated pathways. Notably, these proportions were not based on multiple-testing-corrected associations. Single-cell eQTL mapping associated WTAP's ADHD risk with XCL1-NK cells (OR = 1.445). Bidirectional MR suggested potential reciprocal associations between mental disorders and microbial/metabolite profiles. Pyroptosis demonstrated a tentative statistical association (3.99% explanatory power), though its specific biological role remains undefined. CONCLUSION: This multi-omics integration generates a hypothesis regarding a potential m6A-microbiota-metabolite axis that may be associated with mental disorders, with pyroptosis as a potentially related peripheral factor. Should these associations prove causal, the identified relationships could suggest peripheral intervention nodes, while combinatorial targeting might provide directions for preventive psychiatry. Experimental validation is required to confirm the biological mechanisms implied by these genetic associations.
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IL-1β pathway-dependent regulation of glutamate receptor activity by gut microbiota in bipolar depression.
OBJECTIVES: Neuroinflammation may disrupt neurotransmitter signaling. This study investigated whether gut microbiota-induced neuroinflammation can regulate glutamate pathways in bipolar disorder (BD). METHODS: Fecal microbiota transplantation (FMT) was performed to observe behavioral changes in the antibiotic-treated C57BL/6J male mouse model of bipolar depression. Gut microbial structure, circulating, and prefrontal levels of inflammatory factors, microglial activation, and transcription levels of N-methyl- d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4 isoxazole receptor (AMPAR) genes were measured in the "BD" and control mice. Furthermore, the effects of interleukin-1 (IL-1) receptor antagonist (IL-1RA) on the glutamate pathways were assessed. RESULTS: Compared with the control mice, "BD" mice displayed depression-like behaviors, with a lower diversity of gut bacteria and a decreased abundance of certain species. In addition, "BD" mice showed increased levels of inflammatory factors (e.g., IL-1β) in the serum and prefrontal cortex, microglial activation, and changes in the messenger RNA (mRNA) levels of NMDAR and AMPAR. Treatment with IL-1RA partially reversed the behavioral patterns, neuroinflammation, and transcription levels of glutamate receptors. CONCLUSIONS: The findings suggest that gut microbiota may influence glutamate receptor gene expression via an IL-1β-dependent pathway in a mouse model of BD, potentially contributing to neuroinflammatory mechanisms relevant to this disorder.
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Variations in the oral microbiome are associated with depression in young adults.
A growing body of evidence supports an important role for alterations in the brain-gut-microbiome axis in the aetiology of depression and other psychiatric disorders. The potential role of the oral microbiome in mental health has received little attention, even though it is one of the most diverse microbiomes in the body and oral dysbiosis has been linked to systemic diseases with an underlying inflammatory aetiology. This study examines the structure and composition of the salivary microbiome for the first time in young adults who met the DSM-IV criteria for depression (n = 40) and matched controls (n = 43) using 16S rRNA gene-based next generation sequencing. Subtle but significant differences in alpha and beta diversity of the salivary microbiome were observed, with clear separation of depressed and healthy control cohorts into distinct clusters. A total of 21 bacterial taxa were found to be differentially abundant in the depressed cohort, including increased Neisseria spp. and Prevotella nigrescens, while 19 taxa had a decreased abundance. In this preliminary study we have shown that the composition of the oral microbiome is associated with depression in young adults. Further studies are now warranted, particuarly investigations into whether such shifts play any role in the underling aetiology of depression.
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Effects of probiotics on cognitive and emotional functions in healthy older adults: Protocol for a double-blind randomized placebo-controlled crossover trial.
Aging is a process that includes changes in cognitive and emotional functions, as well as changes in the diversity and integrity of gut microbiota. Probiotic treatments have recently been studied as a potential new therapeutic approach to alleviate a wide range of problems in other populations; however, clinical studies in older adults remain insufficient and limited. Thus, the aim of this project is to evaluate the efficacy of a multispecies probiotic formulation as a therapeutic strategy for attenuating the emotional and cognitive decline associated with aging in adults over the age of 55. This is a double-blind randomized placebo-controlled crossover trial involving at least 32 older adults and comparing two conditions: (a) probiotic, providing a multispecies probiotic for 10 weeks (Lactobacillus rhamnosus and Bifidobacterium lactis); and (b) placebo, receiving a harmless substance (potato starch). Despite the increasing use of probiotics for the treatment of cognitive and emotional problems, no study has yet focused on this group, to the best of our knowledge. Therapeutic strategies of the kind outlined in this protocol will help to shed light on the current state of knowledge about this topic, as well as promote health programs tailored to this population, which would encourage active aging and healthy lifestyles. Not only do we expect improvements in the emotional dimension in terms of anxiety, stress, depression, and sleep quality, we also expect improvements in the cognitive dimension in terms of attention, memory, and decreased impulsivity.
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Xiaoyao powder attenuates acetaminophen-induced liver injury through modulating gut microbiota and upregulating GLYAT.
ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyao Powder (XYP) is a traditional Chinese medicine formula first recorded in the Tai Ping Hui Min He Ji Ju Fang. It has been used for over 900 years to treat "liver depression and spleen deficiency" syndrome. Acute drug-induced liver injury (DILI) often presents clinical features analogous to "liver depression and spleen deficiency" syndrome. AIM OF THE STUDY: This study aimed to explore the intestinal mechanism of XYP for treating DILI. MATERIALS AND METHODS: An acetaminophen (APAP)-induced DILI mouse model was established to validate the efficacy of XYP. Levels of aspartate transaminase (AST) and alanine aminotransferase (ALT) were measured, and hematoxylin-eosin (H&E) staining was performed. Subsequently, 16S rRNA gene sequencing and real-time PCR were used to investigate the role of gut microbiota during XYP treatment. In addition, intestinal pseudo-germ-free mouse models were established by antibiotic cocktail (ATB) administration to verify the mechanism of XYP. Intestinal barrier integrity was assessed via histological staining (H&E and periodic acid-Schiff (PAS)), immunohistochemical detection of zonula occludens-1 (ZO-1) and occludin, and measurement of serum lipopolysaccharide (LPS) and diamine oxidase (DAO) levels. Liver glycine-N-acyltransferase (GLYAT) expression was evaluated by Western blotting. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze the components in serum, liver tissues, and XYP decoction. RESULTS: XYP alleviated APAP-induced liver injury in mice in a dose-dependent manner. In the medium-dose XYP (M-XYP) group (ALT: 27.63 ± 0.59 U/L; AST: 35.42 ± 2.93 U/L), ALT and AST activities decreased by 65 % and 70 %, respectively, compared to the model group (ALT: 78.96 ± 1.51 U/L; AST: 118.89 ± 1.66 U/L) (P = 0.01). XYP mitigated APAP-induced disturbances in gut microbiota composition, increased gut microbiota diversity, and elevated the abundance of Lactobacillus acidophilus. Notably, XYP improved liver injury and intestinal barrier function by increasing L. acidophilus abundance. Metabolically, XYP decoction enhanced amino acid metabolism in DILI mice. Compared with ATB-treated DILI mice, XYP elevated serum hippuric acid levels in specific pathogen-free (SPF) DILI mice. L. acidophilus was essential for XYP-mediated upregulation of GLYAT in the liver. Mechanistically, L. acidophilus cooperated with XYP to promote hepatic GLYAT expression in DILI mice. CONCLUSION: XYP alleviated APAP-induced liver injury in mice by increasing L. acidophilus abundance. Notably, L. acidophilus upregulated hepatic GLYAT expression and enhanced intestinal barrier function. These findings provide a potential therapeutic strategy combining XYP with L. acidophilus for managing DILI.
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Assessment of glymphatic dysfunction in ulcerative colitis using DKI-ALPS: An innovative imaging biomarker.
PURPOSE: Ulcerative colitis (UC) is associated with higher anxiety, depression, and cognitive disorders linked to brain glymphatic dysfunction. In this study, we used along-the-perivascular-space (ALPS) index (based on DTI and DKI) to determine if UC relates to glymphatic dysfunction and explore how microbiota dysbiosis and inflammation affect brain glymphatic function. MATERIALS AND METHODS: In this study, 63 patients with UC and 68 healthy controls underwent 3-Tesla MRI scans to evaluate DTI-ALPS and DKI-ALPS index. The protocol included diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) sequences to calculate the ALPS index, which quantifies glymphatic system function. All participants completed cognitive (MMSE) and depression (SAS/SDS) assessments (SAS/SDS). Patients with UC also underwent assessment for inflammation and gut microbiota (based on metagenomic analysis). Data analysis was performed using correlation analysis and linear regression. RESULTS: Patients with UC showed lower DTI-ALPS index (1.25) and DKI-ALPS index (1.40) compared to controls (1.40 vs. 1.69; P < 0.001). In multi-adjusted linear regression models, UC was associated with lower DTI-ALPS index and DKI-ALPS index (β =-0.142 vs.-0.284), with DKI-ALPS showing higher sensitivity. The results remained significant even after stratification by age and sex. The Mayo score correlated negatively with DTI and DKI-ALPS index. The ALPS index correlates with gut microbiota, particularly those involved in butyrate and short-chain fatty acid (SCFA) production. DTI-ALPS index was significantly correlated with ESR (β =-0.003), CRP (β =-0.035), SII (β =-0.062), INFLA (β =-0.010), and SIRI (β =-0.058). We also observed significant correlations between DKI ALPS index and ESR (β =-0.006), CRP (β =-0.051), SII (β =-0.130), INFLA (β =-0.017), SIRI (β =-0.095), IL-6 (β =-0.081) and NLR (β =-0.108). CONCLUSIONS: UC is associated with brain glymphatic dysfunction, correlating with inflammation level. DKI-ALPS serves as a more sensitive method than DTI-ALPS, offering a new approach for managing ulcerative colitis through glymphatic dysfunction.
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The protective effect of probiotic/prebiotic consumption against fatigue in the general population is modulated by BMI: an analysis of mediating and moderating effects based on NHANES.
OBJECTIVES: Fatigue is closely linked to gut microbiota dysbiosis, making probiotics and prebiotics promising candidates for interventions related to fatigue. This study explores the relationship between probiotic/prebiotic consumption and fatigue in the general population, focusing on potential moderating and mediating factors, as most prior research has centered on clinical populations with secondary fatigue. METHODS: This study is a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018, and it included 3,791 US residents without underlying health conditions. Fatigue was assessed using the Patient Health Questionnaire-9 (PHQ-9), and probiotic/prebiotic consumption was evaluated via a 30-day dietary supplement questionnaire. Statistical analyses included weighted logistic regression to examine associations, and mediation/moderation models to assess the roles of BMI, sleep duration, depression scores, and exercise hours. RESULTS: A total of 3,791 participants were included in the study, with 46.6% self-reporting fatigue. Probiotic/prebiotic consumers had a significantly lower fatigue risk (OR = 0.738, 95% CI 0.735-0.741, p < 0.001). Among the mediating and moderating factors analyzed, only BMI was found to weakly but significantly moderate the association between probiotic/prebiotic consumption and fatigue, with higher BMI strengthening the association of probiotics and/or prebiotics intake with reduced fatigue odds (p = 0.039). CONCLUSIONS: These findings indicate that the consumption of probiotics/prebiotics is correlated with a decreased risk of fatigue in the general population, and this association is further reinforced in individuals with a higher BMI.
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Effects of Dendrobium officinale on chronic fatigue in rats: Modulation of tryptophan metabolism.
ETHNOPHARMACOLOGICAL RELEVANCE: Chronic fatigue is a prolonged and persistent state of mental and physical exhaustion that is not readily relieved by rest. Dendrobium officinale Kimura & Migo (D. officinale), a traditional tonic medicinal and edible herb, which have been reported to possess diverse pharmacological activities, including anti-fatigue, immunomodulatory, and gut microbiota-modulating effects. Nevertheless, the effects and underlying mechanisms on chronic fatigue remain largely unexplored. AIM OF THE STUDY: This study aimed to evaluate the effects of D. officinale in a rat model of chronic fatigue induced by complex poor lifestyles, and to elucidate the underlying mechanisms via tryptophan (TRP) metabolic modulation. MATERIALS AND METHODS: A rat model of chronic fatigue was established through complex poor lifestyles, including over stress, inadequate sleep, irregular diet, and over work. The animals were then randomly allocated into five groups: a normal control group (NC), a model control group (MC), and three groups treated with D. officinale water extract (DOW) at doses of 0.1, 0.2, and 0.4 g/kg via oral gavage. After a 4-week intervention, the effects of DOW were subjected by general sign observation, swimming test, elevated plus maze (EPM) and open field tests (OFT). Furthermore, 16S rRNA gene sequencing, LC-MS analysis, Western blotting (WB), and quantitative real-time PCR (qRT-PCR) were performed to assess gut microbiota composition, TRP metabolites, and key metabolic enzymes, thereby elucidating the potential mechanisms by which DOW ameliorates chronic fatigue. RESULTS: DOW markedly improved exercise endurance, alleviated depression-like behaviour as well as attenuated dysregulation of the neuroendocrine-immune (NEI) system. In addition, DOW modulated gut microbiota disturbances and substantially increased the levels of TRP-derived indole metabolites, including indole (IDN), indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-aldehyde (IAld). Meanwhile, it restored the inhibited kynurenine (KYN) metabolic pathway and promoted hepatic expression of key KYN-pathway enzymes, including tryptophan 2,3-dioxygenase 2 (TDO2), kynurenine 3-monooxygenase (KMO), and kynurenine aminotransferase 1 (KAT1), thereby enhancing the production of downstream KYN metabolite, including 3-Hydroxyanthranilic acid (3-HAA), Quinolinic acid (QA), Picolinic acid (PA), and Xanthurenic acid (XA). Correlation analysis further demonstrated that the alleviation of chronic-fatigue-related symptoms and behavioral abnormalities by DOW was strongly associated with its regulation of TRP metabolism. CONCLUSION: DOW effectively alleviated chronic fatigue induced by complex poor lifestyles in rats, and its underlying mechanism may involve modulating the gut microbiota to enhance the synthesis of indole-derived metabolites, and upregulating the expression of key enzymes in the KYN pathway to promote the generation of KYN-derived metabolites, thereby restoring TRP metabolic homeostasis.
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Role of oral-gut microbiota dysbiosis in regulating systemic impairment during age-related obesity: an animal study.
OBJECTIVE: To characterize the systemic effects of high-fat diet (HFD)-induced obesity across different ages, explore the microbiota-related obesity endotype using 16S rRNA sequencing, and identify key microbial genera as candidate markers for longitudinal monitoring and future interventional validation. MATERIALS AND METHODS: Male C57BL/6J mice were randomly assigned to a standard chow diet (SCD) or HFD group, maintained until 4, 12 and 18 months of age as the young, middle-aged and old groups, respectively, at which time animals were euthanized. Systemic effects were evaluated by measuring body weight, Lee's index, glucose-lipid metabolism, liver function, and blood oxygen levels, coupled with behavioral tests for mood and cognitive performance. Blood samples were collected to quantify LPS and Aβ1-42 levels using ELISA. Oral and fecal samples were collected for 16S rRNA sequencing to analyze microbiota diversity and community structure. Differential genera were identified by LEfSe, and those consistently altered in both oral and gut samples were operationally designated as marker genera. Targeted metabolomics was performed to analyze short-chain fatty acids (SCFAs). Correlations were evaluated using Spearman analysis. RESULTS: Compared with SCD, HFD mice showed systemic alterations across all age groups, including progressive obesity, elevated blood lipids and liver enzymes, accompanied by reduced blood oxygen, increased Aβ1-42 and LPS levels, increased anxiety-/depression-like behaviors, and impaired spatial memory. HFD significantly remodeled the alpha/beta-diversity and community structure of oral and gut microbiota, inducing stable enrichment of Romboutsia_B and depletion of beneficial genera (Bifidobacterium, Akkermansia, and Muribaculum). The abundance of Romboutsia_B positively correlated with obesity, blood lipids, liver enzyme levels, hypoxia, and inflammatory markers, but negatively correlated with multiple cognitive-behavioral parameters. Functional prediction and SCFA further profiling indicated that HFD enhanced lipid metabolism and environmental adaptation pathways, while reducing polysaccharide degradation and vitamin metabolism. CONCLUSIONS: Long-term HFD is associated with systemic remodeling of the oral-gut-liver-brain axis across ages. Romboutsia_B, a pro-inflammatory-associated genus stably enriched in the oral and gut across all age groups, holds potential as a noninvasive microbial biomarker and candidate target for future intervention studies for obesity and its liver-brain comorbidities.
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Co-supplementation of camelina oil and a prebiotic is more effective for in improving cardiometabolic risk factors and mental health in patients with NAFLD: a randomized clinical trial.
This trial evaluated the effects of co-supplementing Camelina sativa oil (CSO) and a prebiotic as modulators of the gut microbiota on cardiometabolic risk factors and mental health in NAFLD patients. In all, 44 subjects with NAFLD were allocated to either an intervention (20 g d-1 CSO + resistant dextrin) or a placebo (20 g d-1 CSO + maltodextrin) group and received a calorie-restricted diet (-500 kcal d-1) for 12 weeks. Fasting plasma levels of gucose, insulin, hs-CRP, endotoxin, antioxidant enzyme activity, total antioxidant capacity (TAC), malondialdehyde (MDA), 8-iso-prostaglandin F2α, and uric acid were measured at the baseline and post-intervention. The depression, anxiety and stress scale (DASS) and the general health questionnaire (GHQ) were used to assess mental health. Co-supplementing CSO and resistant dextrin significantly decreased the level of insulin concentration (-0.84 μU ml-1, p = 0.011), HOMA-IR (-0.27, p = 0.021), hs-CRP (-1.25 pg ml-1, p = 0.023), endotoxin (-3.70 EU mL-1, p = 0.001), cortisol (-2.43, p = 0.033), GHQ (-5.03, p = 0.035), DASS (-9.01, p = 0.024), and MDA (-0.54 nmol mL-1, p = 0.021) and increased the levels of TAC (0.16 mmol L-1, p = 0.032) and superoxide dismutase (106.32 U g-1 Hb, p = 0.45) in the intervention group compared with the placebo group. No significant changes were observed in the levels of other biomarkers. Co-supplementing CSO and resistant dextrin in combination with a low-calorie diet may improve metabolic risk factors and mental health in NAFLD patients.