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Fecal microbiota transplantation fails to impart the benefits of circadian-dependent intermittent fasting following ischemic stroke.
Intermittent fasting (IF) is known to induce significant ischemic tolerance. Diet is a major proponent of gut microbiota, and gut microbial dysbiosis plays a role in post-stroke brain damage. Hence, we currently evaluated whether IF-mediated ischemic tolerance is mediated by gut microbiota. Additionally, circadian cycle is known to modulate post-ischemic outcomes, and thus we further evaluated if gut microbiota would be influenced by prophylactic IF during the inactive phase (fasting during daytime; IIF) or active phase (fasting during nighttime; AIF). The AIF, but not IIF, cohort showed a significantly decreased fecal Firmicutes/Bacteroidetes ratio compared with the ad libitum (AL) cohort. Moreover, the levels of gut microbiota-derived metabolites butyrate and propionate decreased in AL cohort following focal ischemia, whereas they increased in AIF cohort. However, fecal microbiota transplantation (FMT) from IIF or AIF cohort had no significant effects on post-ischemic motor and cognitive function recovery, anxiety-, and depression-like behaviors compared with FMT from AL cohort. Furthermore, FMT from IIF or AIF cohort did not influence the post-ischemic infarct volume, atrophy volume or white matter damage. Overall, the current findings indicate that the beneficial effects of IF after focal ischemia are not mediated by the gut microbiota.
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Intervening Mechanisms of Amitriptyline Combined With Domperidone on Functional Dyspepsia Rats.
OBJECTIVES: The long-term recurrent symptoms of functional dyspepsia (FD) and the prolonged course of the disease lead to varying degrees of psychological disorders in patients. The study focuses on investigating the effects of the psychological drug amitriptyline on FD rats, aiming to provide a basis for the mechanism of action in treating FD from a clinical psychological perspective. METHODS: A rat model of FD was used to assess gastric emptying, intestinal propulsion, visceral sensitivity, and behavioral states after treatment with amitriptyline, domperidone, or both drugs. The concentrations of 5-hydroxytryptamine (5-HT) and the expression of related signaling molecules were measured using ELISA, RT-qPCR, and Western blot. Gastrointestinal motility was also evaluated through muscle perfusion experiments, and the composition of gut microbiota was analyzed using 16S rRNA sequencing. RESULTS: Amitriptyline, either alone or combined with domperidone, improved FD rat behavioral scores, food intake, and mental status in FD rats. It increased 5-HT concentrations in plasma and gastrointestinal tissue, decreased visceral sensitivity, and altered the expressions of 5-HT2B receptor, phospholipase C-β2, IP3 receptor, and calcium-activated chloride channel anoctamin 1 (ANO1) in the gastrointestinal tissues. Although amitriptyline had no significant effect on in vivo gastric or intestinal transit rates, it significantly inhibited the contractile activity of isolated gastrointestinal muscle strips and exhibited anticholinergic effects. Additionally, amitriptyline either alone or combined with domperidone increased the relative abundance of Actinomycetota and specifically the Eggerthellales order in the gut microbiota. CONCLUSIONS: The combination of amitriptyline and domperidone relieves anxiety and depression, improves gastrointestinal motility by targeting the 5-HT2BR, PLCβ2, and IP3R signaling pathways, and modulates the gut microbiota. This integrated approach alleviates FD symptoms through multiple mechanisms and pathways, presenting a promising therapeutic strategy.
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Towards molecular diagnostics of parental alienation.
High-conflict parental divorce can result in parental alienation (PA), leading to chronic psychological stress in children that adversely affects their mental and physical health. This stress may manifest as anxiety, depression, eating disorders, immune dysfunction, and cardiovascular, neurological, endocrine, or gastrointestinal issues. The inconsistent legal recognition of PA highlights the need for objective diagnostic tools to inform judicial decisions. We propose a panel of molecular biomarkers, derived from well-established indicators of chronic stress, to address the limited data specific to PA. This panel targets hypothalamic-pituitary-adrenal (HPA) axis activation, neurotransmitter dysregulation, inflammation, oxidative stress, epigenetic modifications, and gut microbiota dysbiosis. Interdisciplinary collaboration among researchers, general practitioners, and legal professionals is crucial to validate and implement this panel, ultimately enhancing child welfare through early intervention.
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Molecular Links Between Metabolism and Mental Health: Integrative Pathways from GDF15-Mediated Stress Signaling to Brain Energy Homeostasis.
The relationship between metabolic dysfunction and mental health disorders is complex and has received increasing attention. This review integrates current research to explore how stress-related growth differentiation factor 15 (GDF15) signaling, ceramides derived from gut microbiota, and mitochondrial dysfunction in the brain interact to influence both metabolic and psychiatric conditions. Evidence suggests that these pathways converge to regulate brain energy homeostasis through feedback mechanisms involving the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. GDF15 emerges as a key stress-responsive biomarker that links peripheral metabolism with brainstem GDNF family receptor alpha-like (GFRAL)-mediated anxiety circuits. Meanwhile, ceramides impair hippocampal mitochondrial function via membrane incorporation and disruption of the respiratory chain. These disruptions may contribute to sustained pathological states such as depression, anxiety, and cognitive dysfunction. Although direct mechanistic data are limited, integrating these pathways provides a conceptual framework for understanding metabolic-psychiatric comorbidities. Furthermore, differences in age, sex, and genetics may influence these systems, highlighting the need for personalized interventions. Targeting mitochondrial function, GDF15-GFRAL signaling, and gut microbiota composition may offer new therapeutic strategies. This integrative perspective helps conceptualize how metabolic and psychiatric mechanisms interact for understanding the pathophysiology of metabolic and psychiatric comorbidities and highlights therapeutic targets for precision medicine.
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Fructose malabsorption induces dysbiosis and increases anxiety in male human and animal models.
Excessive fructose intake is a growing public health concern, yet many individuals have a limited capacity to absorb typical dietary levels, leading to chronic fructose malabsorption and intestinal spillover. In animal models, this spillover disrupts the gut microbiota, but its impact in humans remains unexplored. We hypothesized that fructose malabsorption-induced dysbiosis contributes to peripheral inflammation, which, together with neuroinflammation, plays a role in mood disorders. This study investigates the link between fructose malabsorption, gut microbiota, and mood disorders in a human cohort, and explores their association with neuroinflammation in a Glut5 knockout (GLUT5_KO) mouse model of fructose-malabsorption. In a human cohort of male healthy volunteers, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS), IL8 and TNFα levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, GLUT5_KO male mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed. Sixty percent of volunteers exhibited fructose malabsorption, along with elevated plasma LPS, IL8 and TNFα levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, GLUT5_KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes. These findings highlight the complex interplay between dietary fructose, gut microbiota, low grade inflammation and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions.
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Vitamin B12-producing Cetobacterium: An important biomarker linked to snake hibernation.
Hibernation poses significant physiological challenges to the animals, making it an excellent model for investigating the impacts of extreme environment changes on animal health. This study explored the gut microbiota and host metabolism in hibernating snakes using 16S rRNA gene sequencing and untargeted metabolomics. Ten king ratsnakes were divided into active and hibernating groups, and their gut microbial compositions and serum metabolomic profiles were analyzed. Results demonstrated a significant reduction in gut microbial diversity during hibernation, with the abundance of Cetobacterium increasing dramatically from 5.57 % to 49.56 %, establishing it as the predominant genus in hibernating snakes. Metabolomic analysis revealed significant alterations in lipid and amino acid metabolism, with 69 metabolites downregulated during hibernation. Correlation analyses identified Cetobacterium as a central hub in the correction networks, influencing numerous gut microorganisms and showing a strong association with host metabolic depression. In addition to the recognized ability to produce vitamin B12 and short-chain fatty acids, this study further confirmed the robust antioxidant ability of snake-derived Cetobacterium somerae strains. These findings highlight the potential role of Cetobacterium in the physiological adaptation of snakes during hibernation and provide a foundation for exploring its applications in reptilian health management.
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Altered fecal microbiota composition in individuals who abuse methamphetamine.
As a severe public health problem, methamphetamine (METH) abuse places a heavy burden on families and society. A growing amount of evidence has indicated communication between gut microbiota and the CNS in drug addiction, with associations to neural, endocrine and immune pathways. Thus, we searched for alterations in the gut microbiota and their potential effects in METH users through 16S rRNA gene sequencing. A decreased Shannon index indicated lower bacterial diversity in the METH users than in the age-matched control group. The gut microbial community composition in the METH users was also altered, including reductions in Deltaproteobacteria and Bacteroidaceae abundances and increases in Sphingomonadales, Xanthomonadales, Romboutsia and Lachnospiraceae abundances. Moreover, the Fusobacteria abundance was correlated with the duration of METH use. Enterobacteriaceae, Ruminococcaceae, Bacteroides, and Faecalibacterium had statistically significant correlations with items related to the positive and negative symptoms of schizophrenia and to general psychopathology in the METH users, and all have previously been reported to be altered in individuals with psychotic syndromes, especially depression. Abstraction, one of the items of the cognitive assessment, was positively related to Blautia. These findings revealed alterations in the gut microbiota of METH users, and these alterations may play a role in psychotic syndrome and cognitive impairment. Although the mechanisms behind the links between these disorders and METH abuse are unknown, the relationships may indicate similarities in the pathogenesis of psychosis induced by METH abuse and other causes, providing a new paradigm for addiction and METH use disorder treatment.
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Chronic stress at the crossroads: Decoding the HPA-SAM-immune-gut axis in inflammatory bowel disease pathogenesis and therapeutics.
Stress, a prevalent factor in modern life, profoundly impacts human health by disrupting immune function and intestinal homeostasis. This review elucidates the mechanisms through which stress dysregulates the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal medulla (SAM) axes, leading to altered glucocorticoid and catecholamine levels that impair immune responses and promote inflammation. Chronic stress exacerbates gut microbiota dysbiosis, reduces microbial diversity, and compromises intestinal barrier integrity, contributing to conditions like inflammatory bowel disease (IBD). Stress-induced HPA axis dysfunction and neuroendocrine alterations further aggravate IBD pathogenesis by enhancing pro-inflammatory pathways (e.g., IL-6/STAT3) and disrupting mucosal immunity. Clinical evidence highlights bidirectional links between psychological stress and IBD progression, with stress exacerbating symptoms and IBD increasing susceptibility to anxiety and depression. Therapeutic strategies, including probiotics, anti-inflammatory agents, and psychological interventions (e.g., yoga), show promise in mitigating stress-related gut inflammation and improving patient outcomes. This synthesis underscores the necessity of integrating psychological care with conventional treatments to address the multifaceted interplay between stress, immunity, and gut health in IBD management.
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Biomolecular Aspects of Reelin in Neurodegenerative Disorders: An Old Candidate for a New Linkage of the Gut-Brain-Eye Axis.
Recent findings highlight that Reelin, a glycoprotein involved in neural development, synaptic plasticity, and neuroinflammation, plays some specific roles in neurodegenerative disorders associated with aging, such as age-related macular degeneration (AMD) and Alzheimer's disease (AD). Reelin modulates synaptic function and guarantees homeostasis in neuronal-associated organs/tissues (brain and retina). The expression of Reelin is dysregulated in these neurological disorders, showing common pathways depending on chronic neurogenic inflammation and/or dysregulation of the extracellular matrix in which Reelin plays outstanding roles. Recently, the relationship between AMD and AD has gained increasing attention as they share many common risk factors (aging, genetic/epigenetic background, smoking, and malnutrition) and histopathological lesions, supporting certain pathophysiological crosstalk between these two diseases, especially regarding neuroinflammation, oxidative stress, and vascular complications. Outside the nervous system, Reelin is largely produced at the gastrointestinal epithelial level, in close association with innervated regions. The expression of Reelin receptors inside the gut suggests interesting aspects in the field of the gut-brain-eye axis, as dysregulation of the intestinal microbiota has been frequently described in neurodegenerative and behavioral disorders (AD, autism, and anxiety and/or depression), most probably linked to inflammatory, neurogenic mediators, including Reelin. Herein we examined previous and recent findings on Reelin and neurodegenerative disorders, offering findings on Reelin's potential relation with the gut-brain and gut-brain-eye axes and providing novel attractive hypotheses on the gut-brain-eye link through neuromodulator and microbiota interplay. Neurodegenerative disorders will represent the ground for a future starting point for linking the common neurodegenerative biomarkers (β-amyloid and tau) and the new proteins probably engaged in counteracting neurodegeneration and synaptic loss.
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Updates on the Role of Probiotics against Different Health Issues: Focus on Lactobacillus.
This review article is built on the beneficial effects of Lactobacillus against different diseases, and a special focus has been made on its effects against neurological disorders, such as depression, multiple sclerosis, Alzheimer's, and Parkinson's disease. Probiotics are live microbes, which are found in fermented foods, beverages, and cultured milk and, when administered in an adequate dose, confer health benefits to the host. They are known as "health-friendly bacteria", normally residing in the human gut and involved in maintaining homeostatic conditions. Imbalance in gut microbiota results in the pathophysiology of several diseases entailing the GIT tract, skin, immune system, inflammation, and gut-brain axis. Recently, the use of probiotics has gained tremendous interest, because of their profound effects on the management of these disease conditions. Recent findings suggest that probiotics enrichment in different human and mouse disease models showed promising beneficial effects and results in the amelioration of disease symptoms. Thus, this review focuses on the current probiotics-based products, different disease models, variable markers measured during trials, and evidence obtained from past studies on the use of probiotics in the prevention and treatment of different diseases, covering the skin to the central nervous system diseases.