From Gut Microbiota to Synaptic Plasticity: Mechanisms Shaping Cognitive Function and Brain Disorders.

The Microbiota-Gut-Brain Axis in Neuropsychiatric Disorders: Mechanisms, Advances, and Clinical Applications.

Neuropsychiatric disorders are increasingly recognized as systemic conditions arising from dynamic interactions within the gut-brain-immune network. The Microbiota-Gut-Brain Axis (MGBA) serves as a central regulatory system orchestrating neurodevelopment, neural homeostasis, and immune-metabolic balance. This review summarizes evidence across seven major neuropsychiatric disorders, Depression, Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, Alzheimer's disease, Schizophrenia, Anxiety and Obsessive Compulsive Disorder, demonstrating that dysregulation of the MGBA constitutes a shared pathological mechanism. On this common basis, we delineate disorder specific neurochemical and immunological features and highlight the clinical potential of microbiota-targeted interventions. Moreover, psychotropic medications profoundly alter microbial physiology, influencing bacterial growth and metabolism, thereby complicating interpretation of MGBA-disease relationships. Future research should define strain-specific therapeutic actions and integrate multi-omics approaches to unravel causal pathways, ultimately enabling precision microbiome modulation in neuropsychiatric medicine.

Intestinal microbiota in neurodegeneration and ageing: Mechanisms, pathways, and therapeutic interventions.

Microbiota-gut-brain axis in autism spectrum disorder: integrating brain structure, function, and transcriptomics.

Growing evidence indicates that disruption of the microbiota-gut-brain (MGB) axis is a key factor in autism spectrum disorder (ASD), affecting neurodevelopment, neural circuit function, and behavior. This review synthesizes multidisciplinary data to clarify mechanistic links between the MGB axis and ASD and to evaluate microbiota-targeted therapeutic strategies. We conducted a narrative synthesis of clinical and translational studies, including human cohort and case-control investigations, animal models, multi-omics analyses, immune profiling, multimodal brain assessments (structural/functional MRI and transcriptomics), and interventional trials. Emphasis was placed on evidence of microbiota-brain associations, intervention outcomes, and methodological limitations. Key findings reveal that individuals with ASD commonly exhibit gut microbiome dysbiosis and altered metabolomic signatures that can influence central nervous system function; three core bidirectional signaling routes link gut microbes to brain outcomes-microbial metabolite production (e.g., short-chain fatty acids, tryptophan metabolites), immune-mediated pathways, and neuroendocrine-vagal communication. Accumulating data associate ASD-related microbial profiles with changes in brain structure, functional connectivity, and transcriptomic patterns, supporting a mechanistic role for the MGB axis in ASD phenotypes. Microbiota-targeted interventions show promising effects on gastrointestinal symptoms, metabolic biomarkers, and selected behavioral measures in small studies, but results are heterogeneous and current evidence is insufficient for widespread clinical application. Integrating multimodal neuroimaging with multi-omics and machine learning provides a promising framework to identify reproducible microbial-brain biomarkers for early detection, clinical subtyping, and stratified treatment. Key challenges include methodological heterogeneity, limited causal inference, small and heterogeneous cohorts, and ethical/safety concerns for pediatric interventions. The MGB axis is a plausible pathogenic mechanism and therapeutic target in ASD. Translating mechanistic insights into precision clinical applications requires standardized, multicenter, longitudinal deep-phenotyping studies that combine multimodal imaging, comprehensive multi-omics, rigorous randomized trials, and careful ethical oversight.

Metabolic Outputs of the Gut Microbiome: Implications for Epilepsy

Highlights What are the main findings? Microbiota-derived metabolites function as critical cellular mediators of gut–brain communication, influencing neurotransmission, neuroinflammatory signaling, and blood–brain barrier integrity. Emerging evidence identifies multiple microbiota-derived molecules, including neurotransmitters, vitamins, and polyphenol metabolites, as key modulators of neuronal hyperexcitability and seizure-related pathways. What are the implications of the main findings? Understanding how microbial metabolites regulate cellular processes in the brain may reveal previously unrecognized mechanisms underlying epileptogenesis. Microbiome-targeted interventions designed to restore beneficial metabolite production have the potential to become a new class of precision therapies for epilepsy and other neurological disorders. Abstract Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 million people worldwide, and despite the availability of anti-seizure medications (ASMs), approximately 30% of patients develop drug-resistant epilepsy. Current ASMs primarily suppress seizures rather than prevent disease progression, highlighting the need for alternative therapeutic strategies. In this context, increasing evidence supports a role for microbiota-dependent pathways in modulating seizure activity and treatment responsiveness. However, the mechanistic basis of these interactions remains incompletely understood. Methods: This narrative review synthesizes findings from the existing literature to examine the role of microbiota-derived metabolites, including neurotransmitters, vitamins, and the polyphenol metabolite S-equol, in gut–brain communication relevant to epilepsy. Evidence was drawn from both preclinical animal models and clinical studies to provide an integrated, mechanistic perspective on how these pathways may influence central nervous system function and seizure susceptibility. Emphasis was placed on studies describing molecular, metabolic, and signaling mechanisms linking the gut microbiome to epileptogenesis and treatment response. Results: Current evidence indicates that communication between the gut and CNS occurs through neural pathways, such as the vagus nerve, as well as through circulating microbial metabolites. These metabolites can cross the intestinal barrier and, in some cases, the blood–brain barrier (BBB), serving as key mediators of host–microbiota signaling. Emerging studies suggest that while some microbial metabolites may directly influence neuronal hyperexcitability and seizure susceptibility, others likely exert secondary or modulatory effects through broader metabolic and immune pathways. However, the precise mechanisms underlying these interactions remain incompletely understood. Conclusions: Some microbial-derived metabolites may serve as promising biomarkers and mechanistic mediators of epilepsy; however, further investigation is needed to define the molecular and cellular pathways through which these metabolites influence seizure susceptibility and epileptogenesis.

THE GUT–BRAIN AXIS IN NEURODEGENERATIVE DISEASES: LINKING MICROBIOTA DYSBIOSIS, BARRIER DYSFUNCTION, AND NEUROINFLAMMATION

Neurodegenerative diseases (NDDs), including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, are characterized by progressive neuronal dysfunction and loss. Neuroinflammation, immune dysregulation, oxidative stress, and mitochondrial dysfunction are increasingly recognized as interconnected mechanisms in disease progression. The gut–brain axis provides a bidirectional link between the gastrointestinal tract and central nervous system through neural, immune, endocrine, and metabolic pathways. Gut microbiota dysbiosis may contribute to neurodegeneration through impaired intestinal barrier integrity, altered microbial metabolites, systemic inflammation, and blood–brain barrier dysfunction. Changes in short-chain fatty acids, tryptophan-derived metabolites, bile acids, and microbial products such as lipopolysaccharide may modulate immune and glial signaling, including TLR4/NF-κB and NLRP3 pathways. Evidence is particularly prominent in Alzheimer’s and Parkinson’s diseases, although microbial alterations remain heterogeneous across studies. The gut–brain axis represents a potentially modifiable interface linking microbial dysbiosis and neuroinflammation. Microbiome-targeted interventions show promising but inconsistent results. Further integration of microbiomics, metabolomics, immunophenotyping, and longitudinal clinical data is needed to establish causality and advance precision strategies for neurodegenerative diseases.

The Microbiota–Gut–Brain Axis in Autism Spectrum Disorder: From Pathophysiological Mechanisms to Precision Therapeutics, A Comprehensive Review

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by persistent social communication deficits and restricted, repetitive behaviors. Gastrointestinal symptoms are common and often correlate with symptom severity, implicating the microbiota–gut–brain axis as a potential mechanism linking gut dysbiosis with neurodevelopment through neural, immune, endocrine, and metabolic pathways. This review summarizes current evidence on alterations in the gut microbiota in ASD and critically examines whether these changes contribute to disease pathogenesis or represent secondary effects. It highlights recent advances in multi-kingdom microbiome profiling, metabolomics, mechanistic studies of neuroinflammation, and neurotransmitter signaling and considers major confounding factors, including diet, medication, and gastrointestinal comorbidities. Emerging studies emphasize microbial function over taxonomy. In the largest multi-kingdom analysis, 31 microbial and functional markers distinguished children with ASD from neurotypical controls with an area under the curve of 0.91, driven primarily by ubiquinol-7 and thiamine diphosphate biosynthesis pathways rather than individual taxa. Metabolomic and genetic studies suggest that microbial metabolites may mediate behavioral effects. Microbiota transfer therapy and fecal microbiota transplantation have demonstrated sustained improvements in gastrointestinal and behavioral outcomes, whereas probiotics and dietary interventions have produced inconsistent results. Although alterations in the gut microbiome are consistently observed in ASD, specific microbial signatures remain heterogeneous, and causality remains unproven. Functional microbial pathways appear more informative than taxonomic composition for biomarker discovery and therapeutic development. Future progress requires prospective birth cohorts, pre-diagnostic sampling, mechanistic validation, and adequately powered randomized trials before microbiome-based diagnostics and therapies can be translated into clinical practice.