Search Results (1,889)

Cirrhosis, accounting for 2.4% of global mortality in 2019, represents a leading cause of death in chronic liver disease. Hepatic encephalopathy (HE), a decompensated complication of cirrhosis, is associated with a median survival of only 0.92 years post-diagnosis. Current screening methods relying on neuropsychological tests (e.g., Psychometric Hepatic Encephalopathy Score, PHES) have limitations such as time-consuming procedures and subjective interpretation, potentially delaying diagnosis. To address this, we integrated four cirrhotic transcriptomic cohorts (GSE41919, GSE57193, GSE139602, and GSE15654) and employed an integrated algorithm (LASSO [Least Absolute Shrinkage and Selection Operator]–RFE [Recursive Feature Elimination]–random forest) to identify HE-specific biomarker genes. Ultimately, we developed an HE risk-prediction system centered on eight HE-specific marker genes, namely, PRB2, TUBA1C, NPC2, LRRC32, TLN1, SOX9, SERPINA3 and RNASE4. Based on these genes, an XGBoost (eXtreme Gradient Boosting)-based HE risk stratification model was constructed, and SHAP (SHapley Additive exPlanations) analysis was further introduced to address the “black-box” limitation of conventional machine learning models and to improve the interpretability. The finalized eight-gene system enables accurate, efficient, and interpretable HE risk assessment in patients with cirrhosis. Functional characterization through gene set enrichment analysis and structural equation modeling further revealed that these marker genes converge on four interconnected biological processes, namely, metabolic homeostasis, synaptic and neural transmission, immune inflammatory signaling, and hepatic detoxification, which collectively reflect the gut–liver–brain axis disruption central to HE pathogenesis. This dual-model system, incorporating both cirrhosis progression and survival prognosis, provides a reliable and clinically applicable tool for early HE risk warning and stratification, reducing the limitations of traditional neuropsychological screening and offering a translational foundation for timely intervention and prognostic optimization in high-risk cirrhotic patients. Full article

Background/Objectives: Gastrointestinal dysmotility (GID) is a frequent non-motor manifestation of Parkinson’s disease (PD). However, its peripheral electrophysiological characteristics, as well as the underlying neural mechanisms within the brain–gut axis, remain insufficiently understood. This study aimed to delineate spatiotemporal abnormalities in gastrointestinal pacing activity in PD and to explore their associations with cerebral functional connectivity (FC). Methods: Multichannel electrogastroenterography (EGEG) recordings, including both preprandial and postprandial states from gastric (leads 1–4) and intestinal (leads 5–8) regions, were obtained from patients with PD and healthy controls (HCs), alongside resting-state functional MRI (rs-fMRI). The striatal–thalamic circuit was selected as the seed region for FC analysis. Between-group differences in EGEG-derived spatiotemporal metrics were assessed using analysis of covariance (ANCOVA), while FC differences were examined using two-sample t-tests. Partial correlation analyses were conducted to evaluate associations among neuroimaging measures, aberrant gastrointestinal electrophysiological indices, and clinical variables. Regional specificity of correlations was further tested by comparing dependent correlation coefficients. In addition, multivariate brain–gut connectivity was assessed using partial canonical correlation analysis (pCCA) with 1000 permutation tests. Results: Relative to HCs, PD patients exhibited a significant reduction in the proportion of normal slow waves in both gastric and intestinal regions during preprandial and postprandial states (pFDR < 0.05). FC analysis revealed increased connectivity between the left thalamus and right insula in PD, whereas interhemispheric connectivity of the caudate nuclei and putamina was significantly reduced. Additionally, FC between the left pallidum and left precentral gyrus was attenuated in the PD group. Partial correlation analysis demonstrated a positive association between postprandial normal slow-wave fraction and interhemispheric caudate connectivity (r = 0.63, pFDR = 0.047). Furthermore, left thalamus–right insula connectivity correlated with both total Non-Motor Symptoms Scale (NMSS) scores (r = 0.57, pFDR = 0.042) and gastrointestinal subscale scores (r = 0.63, pFDR = 0.037). At the multivariate level, pCCA revealed a strong association between lentiform nucleus connectivity and preprandial gastric slow-wave rhythms (canonical r = 0.892, p = 0.004). Conclusions: In PD, caudate nucleus FC shows a preferential association with gastric rather than intestinal electrophysiological activity. Multivariate analyses further demonstrate a significant network-level association between lentiform nucleus connectivity and baseline gastric pacing rhythms, extending regional findings to a broader network interaction. Together, these results provide multimodal correlational evidence reflecting parallel central and peripheral alterations in PD, highlighting synchronized alterations in central networks and peripheral gastrointestinal rhythmicity. Full article

Age-related alterations in the gut microbiota contribute to chronic low-grade inflammation, immune dysregulation, metabolic dysfunction, frailty, sarcopenia, and cognitive decline. Dietary polyphenols and fermentable fiber modulate microbial composition and metabolism, promoting the production of bioactive metabolites, including short-chain fatty acids, secondary bile acids, indole derivatives, and urolithins, which regulate intestinal barrier integrity, immune homeostasis, mitochondrial function, and gut–organ communication. This narrative review critically synthesizes evidence from experimental studies, observational cohorts, randomized controlled trials, systematic reviews, and meta-analyses to examine microbiota-mediated mechanisms linking these dietary components to healthy aging within the geroscience framework. Although mechanistic evidence is compelling, translation into clinically meaningful aging outcomes remains limited because most intervention studies are small and heterogeneous and primarily rely on surrogate biomarkers. Current evidence supports polyphenol- and fiber-rich dietary patterns as biologically plausible strategies for promoting healthy aging through modulation of the gut microbiota; however, establishing causal relationships will require standardized microbiome methodologies, validated microbiome-derived biomarkers, integrated multi-omics approaches, and adequately powered longitudinal studies and randomized controlled trials. Full article

Microplastics and nanoplastics (MNPs) are emerging environmental pollutants due to their persistence and bodily accumulation. Recently, functional foods have received much attention for their ability to reverse or block MNP damage for therapeutic purposes and the potential risk of developing oral–gut–brain axis disorders. Among these, artichoke, spirulina algae, Opuntia ficus-indica, pterostilbene, hydroxycinnamic acids, and quinic acid are rich sources of polyphenols. These bioactive ingredients, especially when combined with probiotics and prebiotics, exhibit significant antioxidant and anti-inflammatory potential by activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and cellular resilience enzymes. Nrf2 activation enhances cellular resilience response, and it may preserve oral epithelial barrier (OEB), intestinal epithelial barrier (IEB), and blood–brain barrier (BBB) integrity, while modulating oral pathogens, gut microbial dysbiosis, and neuroinflammatory processes. However, most of the available evidence supporting these mechanisms derives from in vitro and animal studies, whereas clinical evidence in humans remains limited. Perturbations of Nrf2 due to circulating MNPs may exacerbate selective susceptibility to oral, gut, and nervous system disorders, including Alzheimer’s disease (AD). Although these findings are biologically plausible, the causal relationships and their clinical relevance have not yet been fully established. This review discusses the role of functional foods in maintaining oral–gut–brain health through Nrf2-mediated mechanisms that may mitigate MNP-induced inflammation and reactive oxygen species (ROS). The review also examines emerging concepts in precision nutritional medicine, including individual variability in dietary responses, microbiome-related factors, and future personalized strategies for populations exposed to MNPs. Finally, current knowledge gaps, the scarcity of human studies, and the challenges in translating preclinical findings into clinical practice are highlighted, emphasizing the need for further translational and clinical research. Full article

Background: The Braak hypothesis proposes that α-synuclein (α-syn) pathology may originate in the gastrointestinal tract and propagate to the central nervous system along the gut–brain axis; however, the precise propagation routes and the factors influencing this process remain controversial. Methods: A gut-originating Parkinson’s disease model was established by injecting α-syn preformed fibrils (PFF) into the duodenal muscularis of C57BL/6J and A53T transgenic mice. Phosphorylated α-synuclein (p-α-syn) pathology, motor behavior, and gut microbiota were assessed, with truncal vagotomy included to evaluate its association with gut-to-brain propagation. Results: In C57BL/6J mice, at 4 months post-injection, p-α-syn deposition was observed in both the duodenal muscular layer and the striatum, accompanied by gut microbiota alterations and motor behavioral deficits. Truncal vagotomy was associated with reduced p-α-syn levels in the brain and alterations in the gut microbiota. In A53T transgenic mice, p-α-syn pathology and neurodegenerative changes were also observed following α-syn PFF injection, though the lack of a genetically matched wild-type control precludes definitive attribution of these phenotypes solely to the A53T transgene. Conclusions: These results align with the Braak hypothesis, showing that gut-derived p-α-syn pathology and associated functional impairments are intimately linked to vagal pathways during their propagation to the brain. Additionally, this gut-origin PD mouse model may serve as a useful tool for future mechanistic investigations. Full article

Dietary patterns increasingly influence research on neurodegenerative diseases, with attention shifting from isolated nutrients to integrative nutritional models. The Amazonian Diet, a biodiversity-based dietary pattern rich in native fruits, seeds, freshwater fish, and cassava-derived foods, is naturally enriched in bioactive compounds including polyphenols, anthocyanins, carotenoids, methylxanthines, selenium, vitamins, and unsaturated fatty acids. This review aimed to investigate the potential relevance of key foods derived from the Amazonian Diet to Parkinson’s disease (PD) by integrating compositional nutritional analysis, multivariate analytical approaches, and mechanistic evidence synthesis. In Stage 1, the composition of 36 Amazonian foods was analyzed using TBCA and FAO data, followed by hierarchical clustering analysis (Ward’s linkage, Euclidean distance). Distinct compositional patterns were identified, highlighting foods with high bioactive diversity, relevant lipid composition, and dietary fiber. In Stage 2, an integrative literature review (PubMed/MEDLINE, SciELO) of in vitro, in vivo, observational, and clinical studies suggested that açaí berry, guaraná, cocoa/cacao, camu-camu, and Brazil nuts contain nutrients and bioactive compounds that intersect with biological pathways implicated in PD, including oxidative stress, mitochondrial dysfunction, and neuroinflammation. However, this review does not evaluate the effects of the Amazonian Diet on PD incidence, progression, symptoms, levodopa response, or biomarkers. Full article

Vascular cognitive impairment (VCI) is a major form of dementia with a complex pathogenesis. Emerging evidence indicates a strong interaction between intestinal mucosal barrier integrity and neuroinflammation, which has been proposed as a candidate contributor in VCI progression. This review comprehensively reviews the initiation and amplification of neuroinflammation in chronic cerebral ischemia. It highlights how impairment of the intestinal mucosal barrier, gut microbiota dysbiosis, and translocation of microbial metabolites contribute to central neuroinflammation via circulatory and neural pathways, suggesting a potential self-sustaining pathological cycle within the gut–brain axis. Furthermore, we analyze the underlying molecular mechanisms, critique current limitations, and suggest promising directions for future research. Full article

Interactions among the gut, brain, and skin are increasingly understood as a systemic regulatory network connecting intestinal activity, neuroimmune communication, and cutaneous homeostasis. Microbiota-derived metabolites, immune mediators, and neuroendocrine pathways can influence central nervous system activity and subsequently regulate skin homeostasis. This review summarizes current evidence on how functional ingredients modulate the gut–brain–skin axis in the context of aging and skin health. Polyphenols, probiotics, and omega-3 fatty acids appear to act through overlapping biological routes, including reshaping microbial communities, supporting epithelial barrier function, regulating immune activity, and limiting oxidative stress. These gut-derived signals may affect the brain through neural, endocrine, and immune pathways, thereby modulating neuroinflammation, hypothalamic–pituitary–adrenal (HPA) axis activity, and neurotransmitter balance. Through brain–skin communication, these changes may influence inflammation, epidermal barrier integrity, collagen remodeling, and skin aging processes. Emerging clinical evidence suggests potential improvements in skin-related outcomes and systemic inflammatory markers; however, studies remain heterogeneous, and integrated assessments of gut, brain, and skin endpoints are limited. Further studies that integrate multi-omics profiling with carefully designed clinical trials will be required to define causal pathways and support the development of evidence-based nutritional approaches targeting this axis. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that develops many years before clinical symptoms appear. The biological changes involved in the earliest stages remain poorly understood, particularly during the preclinical stage. Our previous work has identified gradual gut microbial and metabolic changes during this stage, suggesting these may represent early biological shifts that precede disease progression. Recent studies suggest that the gut microbiome may contribute to early AD processes through its effects on immune regulation, metabolism, and gut–brain communication. Changes in gut microbial composition, including reduced levels of short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibacterium, Roseburia, and Eubacterium, have been reported in individuals with AD and mild cognitive impairment. These microbial alterations have also been linked to disrupted metabolic activity, impaired gut barrier function, and increased neuroinflammatory responses. Diet is an important factor influencing gut microbial composition and metabolic activity. Mediterranean, DASH, and prudent dietary patterns are generally associated with beneficial microbial profiles and increased SCFA production, whereas Western dietary patterns are linked to lower microbial diversity and increased pro-inflammatory taxa. This review summarises the current evidence linking gut microbiota, SCFAs, microbial metabolism, and dietary patterns with early AD pathology, while highlighting important gaps in the existing literature. Full article

Background/Objectives: Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric condition for which current therapies remain inadequate. Probiotics acting on the microbiota–gut–brain axis are a promising preventive strategy, but their benefits are strain-specific. Here we examined whether Lacticaseibacillus paracasei LP36 alleviates lipopolysaccharide (LPS)-induced depression-like behavior in mice, and we characterized its metabolic actions using serum untargeted metabolomics. Methods: Sixty male C57BL/6J mice were randomized into eight groups (58 completed the study and were analyzed) and received saline or LP36 (1 × 10⁸, 1 × 10⁹, or 1 × 10¹⁰ colony-forming units (CFU)/mL) by gavage for 28 days, with LPS (0.5 mg/kg, i.p.) or saline given during the last 10 days. Results: LP36 pretreatment alleviated LPS-induced depression-like behavior in the sucrose preference, forced swimming, and tail suspension tests. Of 2867 annotated serum metabolites, 404 differed between the LPS and control groups, and 601 between the LP36 (10¹⁰)-treated and LPS groups. Among 180 shared differential metabolites, 172 (95.6%) changed in opposite directions, indicating that LP36 mainly reverses LPS-induced metabolic perturbations. KEGG enrichment localized these effects to lipid-related pathways, with lower relative signal intensities of polyunsaturated fatty acids and sphingolipids under LPS and higher relative signal intensities after LP36. In addition, the relative signal intensities of several microbiota-derived metabolites, including indoles, kynurenines, and secondary bile acids, shifted toward control-group values after LP36 intervention, which might reflect a contribution of the gut microbiota. Conclusions: LP36 is thus a candidate psychobiotic that may alleviate depression by reshaping gut microbiota-related metabolism and the associated lipid remodeling. Full article

Background: The oral microbiome plays a fundamental role in maintaining local and systemic health during childhood, a developmental period characterized by dynamic microbial, immune, and neuroendocrine maturation. Increasing evidence suggests that oral dysbiosis may influence gut microbiota composition, systemic inflammation, and neuroinflammatory pathways through the oral–gut–brain axis. Aim: This narrative review aimed to summarize and critically evaluate current evidence regarding the relationship between oral dysbiosis, gut microbial alterations, systemic inflammation, and neurodevelopmental processes in pediatric populations. Methods: A search of the literature was conducted using PubMed, Scopus, and Web of Science, including studies published between January 2016 and April 2026. Eligible studies included randomized controlled trials, observational studies, and reviews investigating at least one component of the oral–gut–brain axis in children or adolescents. Results: Current evidence supports a biological interaction between oral and gut microbiota through microbial translocation and immune-mediated mechanisms. Oral dysbiosis may contribute to gut microbial imbalance, intestinal barrier dysfunction, and systemic low-grade inflammation. Altered gut microbiota has been associated with neuroinflammatory signaling, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, and adverse neurodevelopmental outcomes. Furthermore, pediatric randomized controlled trials suggest that probiotics and synbiotics can modulate oral and gut microbial composition, improve selected inflammatory and immune biomarkers, and reduce salivary cortisol levels. Conclusions: The oral–gut–brain axis represents a promising framework for understanding the systemic consequences of oral dysbiosis during childhood. However, direct evidence integrating oral, intestinal, immunological, and neurodevelopmental outcomes remains limited, highlighting the need for longitudinal and multidisciplinary pediatric studies. Full article

Psychological stress arises when individuals perceive demands as exceeding their capacity to cope. Social stress can be acute, such as giving a presentation, producing transient increases in heart rate, blood pressure, and neuroendocrine activation, or chronic, in which stressors persist over extended periods. Chronic psychosocial stress disrupts immune homeostasis and contributes to anxiety, depression, and post-traumatic stress, while also increasing risk for infections, inflammatory and autoimmune diseases, cardiovascular disease, metabolic dysfunction, and cancer. Persistent stress engages interconnected neuroendocrine–immune networks, including the hypothalamic–pituitary–adrenal axis, the sympathetic–adrenomedullary system, and the gut microbiota–brain–immune axis, leading to sustained glucocorticoid and catecholamine signaling, gut dysbiosis, impaired barrier integrity, and altered microbial metabolite profiles. In this review, we summarize the molecular and cellular mechanisms by which these axes remodel innate and adaptive immunity and shape disease susceptibility. Using social defeat and social isolation in mice as model systems, we highlight how chronic social stress reprograms immune responses in key tissues, including the lung, brain, and gut. Full article

γ-Aminobutyric acid (GABA) is a non-proteinogenic amino acid that acts as a major signaling molecule across the nervous, cardiovascular, and immune systems. While GABA has historically been produced via chemical synthesis or plant extraction, microbial fermentation using lactic acid bacteria (LAB) provides a safe, sustainable, and food-grade alternative. This review details the recent progress of LAB-derived GABA, covering the workflow from strain selection to functional food applications. We discuss how modern screening methods combine high-throughput phenotypic testing with genomic mining of the gad operon to efficiently identify high-yielding strains. The biochemical mechanisms of the GABA shunt are also explained, alongside recent CRISPR-based metabolic engineering efforts designed to bypass natural yield limits. Furthermore, we address practical industrial challenges—such as the poor proteolytic ability of key producers like Levilactobacillus brevis—and evaluate viable solutions, including symbiotic co-cultures and optimized downstream purification steps. The review then summarizes the specific health benefits of dietary LAB-derived GABA, focusing on its ability to relieve anxiety via the microbiota-gut–brain axis, control blood pressure, and regulate immunity. Finally, we analyze the current regulatory and sensory hurdles, highlighting how integrating multi-omics data can help establish LAB-derived GABA as a reliable ingredient for functional foods and personalized nutrition. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ deposition, tau hyperphosphorylation, and neuroinflammation. No effective drugs can slow disease progression. Polysaccharides from traditional Chinese medicine (TCM) exhibit neuroprotective activities (e.g., antioxidant, anti-inflammatory) with good safety. However, their clinical application is limited by low oral bioavailability, poor blood–brain barrier (BBB) permeability, and a pharmacokinetic–pharmacodynamic paradox. The emerging role of the microbiota–gut–brain axis in AD offers a strategy to overcome this paradox. This review summarizes the structural features and classification of TCM polysaccharides (from plants, fungi, and roots/rhizomes) and highlights their anti-AD mechanisms via the gut–brain axis. Acting as prebiotics, these polysaccharides escape upper digestion and are fermented by gut microbiota into short-chain fatty acids (SCFAs) and other metabolites, which enter circulation, cross the BBB, and alleviate AD pathology through metabolic, immune, and neuronal pathways. Outcomes include reduced Aβ deposition and tau phosphorylation, suppressed neuroinflammation, restored synaptic function, and improved cognition. This review provides a theoretical framework for TCM polysaccharide intervention in AD via the gut–brain axis and a pharmacological basis for developing natural product-based AD therapies. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which circadian rhythm disruption (CRD) emerges as both a prodromal feature and a potential pathogenic driver. Elucidating the bidirectional interplay between PD and CRD is essential for identifying early biomarkers and developing chronotherapeutic strategies. We narratively synthesized literature published over the past two decades in PubMed, Web of Science, and CNKI, focusing on molecular mechanisms, clinical manifestations, biomarker development, and interventional studies addressing the PD–CRD interface. In the CRD-PD direction, circadian disruption accelerates dopaminergic neurodegeneration through four convergent mechanisms: (i) REV-ERBα–mediated dysregulation of dopamine biosynthesis and NF-κB/NLRP3-driven neuroinflammation; (ii) impaired sleep-dependent glymphatic clearance of α-synuclein (α-syn); (iii) NAD⁺–SIRT1–BMAL1–PGC-1α axis dysfunction leading to mitochondrial bioenergetic failure; and (iv) C/EBPβ-dependent autophagic rhythm disruption coupled with pro-inflammatory microglial activation, collectively establishing a dual pro-inflammatory–autophagy-suppressive milieu permissive for α-syn aggregation. In the reverse PD-CRD direction, PD pathology destabilizes the circadian system via Braak-stage degeneration of rhythm-regulatory nuclei, retinal dopaminergic denervation attenuating SCN photic entrainment, pineal–melatonin axis suppression, iatrogenic effects of dopaminergic pharmacotherapy, and gut microbiota dysbiosis propagated through the microbiota–gut–brain axis. Emerging multi-modal chronobiomarkers—including peripheral clock gene expression profiles, melatonin secretion patterns, tryptophan–kynurenine metabolites, and gut microbial oscillation signatures—show promise for prodromal diagnosis and disease subtyping. Circadian-targeted precision interventions—encompassing timed bright light therapy, exogenous melatonin, and chronopharmacological interventions—represent a promising translational paradigm for the early identification and management of PD. Full article