Search Results (1,230)

Background: The gut microbiota–brain axis is a highly integrated bidirectional communication network operating through neural, neuroendocrine, immune, and metabolic pathways that maintain central nervous system homeostasis and has emerged as a promising complementary therapeutic target for neurological and neuropsychiatric disorders. Objective: The objective of this study is to systematically evaluate the effects of prebiotics, probiotics, and psychobiotics on gut–brain communication and neurological and behavioral outcomes, including neuroinflammatory markers, HPA-axis parameters, and microbial metabolites. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. Literature searches of PubMed, Scopus, and Google Scholar from 2020 up to March 2026 identified 81 eligible studies (48 preclinical studies, 27 randomized controlled trials, and 6 quasi-experimental clinical studies) from 7358 records. Primary outcomes were systematically categorized into four domains: (1) cognitive performance and social/adaptive behavior; (2) neuroinflammatory markers (TNF-α, IL-6, IL-1β) and barrier integrity; (3) HPA-axis parameters (cortisol/corticosterone); and (4) neuroactive microbial metabolites (short-chain fatty acids and tryptophan derivatives). Methodological quality and risk of bias were assessed independently by two reviewers using the SYRCLE tool for preclinical studies and the Joanna Briggs Institute (JBI) tools for randomized and quasi-experimental clinical trials, with summary visualizations generated using the robvis web application (version 0.3.0). Results: Neurodegenerative diseases (n = 31; 38.3%) and mood disorders (n = 29; 35.8%) were the most frequently investigated conditions. Probiotics predominated (n = 61), followed by prebiotics (n = 12) and synbiotics (n = 8). Descriptively, 92% of included studies reported improvements in at least one evaluated outcome. However, this unweighted observation reflects effect direction rather than clinical magnitude, encompassing primary and secondary endpoints across highly heterogeneous sample sizes, study designs, and risk-of-bias profiles. Conclusions: Microbiota-targeted interventions show promise as complementary strategies for neurological disorders; however, substantial methodological heterogeneity, unstandardized dosing, and the absence of quantitative meta-analysis preclude definitive clinical recommendations. Successful translation will require harmonized protocols, strain-specific functional characterization, and precision microbiota-based trials. Full article

Introduction: Selective serotonin reuptake inhibitors (SSRIs) remain the first-line pharmacological treatment for depressive disorders. However, long-term treatment is often accompanied by weight gain, which negatively impacts medication adherence and cardiometabolic health. Emerging evidence suggests that, in addition to their effects on the central nervous system (CNS), SSRIs may alter the composition and metabolic activity of the gut microbiome, potentially contributing to metabolic disorders. However, the mechanisms linking SSRI-induced microbial changes to weight regulation remain poorly understood. Methods: This narrative review summarizes the current evidence regarding the interactions between SSRIs, the gut microbiome, host metabolism, and weight regulation. Experimental, translational, and clinical studies were critically assessed, with particular emphasis on recent systematic reviews, meta-analyses, randomized controlled trials, and mechanistic studies. A conceptual mechanistic framework was developed based on the available evidence. Results: Experimental and clinical studies indicate that SSRIs can modify both the taxonomic composition and functional activity of the gut microbiota. These changes may influence the production of microbiota-derived metabolites, including short-chain fatty acids, bile acids, and tryptophan metabolites, thereby influencing gut barrier integrity, low-grade inflammation, gut hormone secretion, appetite regulation, and energy homeostasis. Current evidence also suggests that dietary interventions—including increased dietary fiber intake, adherence to a Mediterranean diet, and microbiota-targeted strategies using prebiotics, probiotics, synbiotics, and postbiotics—can beneficially modulate these pathways. However, no randomized, controlled trials have specifically assessed whether such interventions prevent SSRI-associated weight gain. Conclusions: Taken together, the available evidence raises the possibility that gut microbiota alterations may contribute to SSRI-associated weight gain, although this hypothesis has not yet been directly tested in studies evaluating the complete mechanistic pathway. Full article

2′-Fucosyllactose (2′-FL) represents a significant constituent within human milk oligosaccharides, and its benefits for intestinal health and neurodevelopment in infants and young children have been widely recognized. However, the mechanism by which 2′-FL influences early-life behavioral development through the gut–brain axis remains incompletely understood. In this study, we investigated the effects of neonatal 2′-FL supplementation on behavioral development in Sprague-Dawley (SD) rats and explored its potential microbiota-metabolite regulatory mechanisms. After 4 consecutive weeks of oral gavage beginning on postnatal day 2, rats receiving 2′-FL showed significantly increased average movement speed and central-area exploration time in the open field test. From a systemic perspective, 2′-FL lowered blood diamine oxidase (DAO) and D-lactic acid (D-LA) concentrations while elevating colonic mRNA levels of tight junction protein-related genes, consequently enhancing intestinal barrier stability. In addition, 16S rRNA sequencing showed that 2′-FL reshaped the gut microbiota structure and significantly enriched Lactobacillus, Bacteroides, and short-chain fatty acid (SCFA)-associated taxa represented by Lachnospiraceae_NK4A136_group. Untargeted metabolomics revealed that 2′-FL induced systemic metabolic remodeling, characterized by upregulation of the bioactive metabolites dehydroepiandrosterone sulfate (DHEA-S) and deoxycholic acid (DCA), and downregulation of the glucocorticoid-related corticosterone. Western blot validation further showed higher hippocampal protein expression of postsynaptic density protein 95 (PSD95), brain-derived neurotrophic factor (BDNF), and synaptophysin in the 2′-FL group, supporting enhanced synaptic plasticity-related signaling. In summary, neonatal 2′-FL intervention enhanced exploratory behavior and was accompanied by increased hippocampal synaptic plasticity-related protein expression in rats, potentially through coordinated regulation of gut microbiota composition and systemic metabolism. Full article

Background/Objectives: Stress is increasingly recognized as an important modulator of gut microbiome composition and function through the bidirectional microbiota–gut–brain axis. Dietary, psychobiotic, and other lifestyle-oriented interventions have therefore attracted growing interest as potential strategies for simultaneously influencing stress-related outcomes and the gut microbiome. This systematic review aimed to evaluate randomized controlled trials (RCTs) investigating the effects of lifestyle-oriented and psychobiotic interventions on both stress-related outcomes and the gut microbiome in adults. Methods: A systematic literature search was conducted in PubMed, Scopus, and Cochrane CENTRAL for English-language RCTs published between 2016 and April 2026, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies included adults (≥18 years), evaluated lifestyle-oriented or psychobiotic interventions, and reported both gut microbiome-related and stress-related psychological or biological outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Owing to substantial methodological and clinical heterogeneity, findings were synthesized narratively. Results: Twenty-nine RCTs met the eligibility criteria. Interventions included psychobiotic supplementation, dietary interventions and functional foods, and other lifestyle-oriented approaches. Across intervention categories, microbiome responses were heterogeneous, and no single taxonomic or diversity signature consistently characterized trials reporting favorable stress-related outcomes. Nevertheless, recurrent changes involving Bifidobacterium/Bifidobacteriaceae, Lactobacillus/Lactobacillaceae, Faecalibacterium, Roseburia, and members of the Lachnospiraceae/Ruminococcaceae families were identified across several interventions, together with changes in SCFA-related microbial features. Changes in global microbial diversity were inconsistent, and psychological and microbiome responses did not invariably occur in parallel. Overall, the randomized evidence indicates recurrent taxonomic and functional signals rather than a uniform microbiome response across stress-targeting interventions. Substantial heterogeneity in populations, intervention characteristics, study duration, outcome measures, and microbiome assessment methods limited direct comparisons across trials. Conclusions: Current randomized evidence does not identify a uniform microbiome signature associated with successful stress-targeting interventions but suggests partial convergence involving selected bacterial taxa and functional microbial features. The lack of consistent parallel changes in psychological and microbiome outcomes precludes conclusions regarding whether microbiome alterations mediate improvements in stress-related outcomes. Larger, longer-term RCTs incorporating standardized microbiome methodologies and functional microbial analyses are needed to determine the reproducibility and mechanistic relevance of these signals. Full article

Major depressive disorder remains a leading cause of disability worldwide, and the limited efficacy and delayed onset of conventional antidepressants have intensified interest in the microbiota–gut–brain axis as a source of therapeutic targets. Microbiota-associated candidates—short-chain fatty acids, bile acid and tryptophan metabolites, and neuroactive amines—show mood-relevant activity, yet almost none has reached the clinic. This review reframes that gap as a delivery problem. Rather than treating entry into the central nervous system as a universal requirement, we distinguish strategies intended for local intestinal, peripheral systemic, and direct central action, and we argue that delivery is a major but not exclusive translational bottleneck. We outline the barriers these agents face—upper gastrointestinal loss, poor colonic targeting, rapid metabolite turnover, first-pass exposure, and the blood–brain barrier—and synthesize delivery strategies across two fronts. Colon-targeted systems are technically established but have been validated for non-depression indications, whereas brain-directed approaches—bacterial extracellular vesicles, detoxified membrane-coated carriers, receptor-mediated transcytosis, and intranasal routes—reach the brain mainly in selected preclinical models. We foreground a paradox: microbial extracellular vesicles are at once one of the better-documented bio-derived routes for brain exposure in preclinical studies and prominent drivers of neuroinflammation, which defines a risk–opportunity continuum. We close with a route-specific validation roadmap encompassing quantitative exposure, target engagement, chronic efficacy, and safety. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit. Full article

Dysregulation of the microbiota–gut–brain axis has been implicated in Parkinson’s disease (PD), and modulation of the intestinal microbiota may offer a complementary nutritional approach. This study evaluated the preventive attenuation of MPTP-induced PD-like abnormalities by Lactiplantibacillus plantarum SHOU LAC-1 and examined associated microbiota–gut–brain axis-related changes. Forty male C57BL/6J mice were allocated to Control, MPTP, L-DOPA, and SHOU LAC-1 groups (n = 10 per group). SHOU LAC-1 was orally administered at 1 × 10⁹ CFU per mouse per day for 42 days, with MPTP administered during the final 14 days; L-DOPA was administered during the MPTP-treatment period as a positive control. Motor performance and defecatory parameters, nigrostriatal TH and α-SYN immunoreactivity, neurotrophic-support-related gene expression, inflammatory markers, glial-cell-related gene expression, Nrf2-related antioxidant gene expression, colonic histopathology and tight-junction-related gene expression, gut microbiota composition, and serum metabolic profiles were assessed. Compared with MPTP-treated mice, SHOU LAC-1-treated mice showed better motor and defecatory performance, partial preservation of nigrostriatal TH immunoreactivity, reduced α-SYN immunoreactivity, increased neurotrophic-support-related gene expression, lower central and colonic inflammatory markers and glial-cell-related gene expression, increased Nrf2/HO-1/NQO1-related antioxidant gene expression, and comparatively better-preserved colonic morphology with higher tight-junction-related gene expression. 16S rRNA sequencing and untargeted serum metabolomics further showed that SHOU LAC-1 administration was accompanied by changes in gut microbial diversity and composition and serum metabolic profiles. Overall, under this preventive experimental design, SHOU LAC-1 administration was associated with attenuation of multiple MPTP-induced PD-like abnormalities, accompanied by changes in gut microbial and serum metabolic profiles. These preclinical findings are predominantly associative; causal relationships among microbial, metabolic, intestinal, and neurological changes remain to be established, and the translational relevance of SHOU LAC-1 requires further validation. Full article

Fecal microbiota transplantation (FMT) is an emerging microbiome-directed intervention for dogs and cats, but its clinical role remains incompletely defined. This structured narrative review integrates peer-reviewed clinical, mechanistic, methodological, and safety evidence on companion-animal FMT published between 2005 and 2026, with emphasis on efficacy, tolerability, mechanisms, product preparation, donor screening, and research priorities. In dogs, the most consistent clinical signal concerns chronic enteropathy (CE), where observational studies frequently report reduced disease activity scores after FMT, whereas small randomized trials have shown mixed results; however, causal inference remains limited by small sample sizes, heterogeneous diagnostic criteria and treatment protocols, and concurrent therapies. The strongest controlled canine signal comes from parvoviral enteritis, where adjunctive enema-based FMT accelerated diarrhea resolution and shortened hospitalization. Feline data support short-term tolerability and measurable microbiome activity, but clinical efficacy remains preliminary; notably, the first controlled feline chronic enteropathy (CE) trial showed no significant improvement in dysbiosis index or clinical activity scores compared with controls. Proposed mechanisms include donor microbial engraftment, metabolic restoration, immune modulation, and gut–brain and gut–skin axis signaling, although veterinary-specific validation remains limited. Standardized donor screening, batch-level quality control, dose-finding studies, long-term safety surveillance, and adequately powered sham-controlled trials are the main prerequisites for responsible clinical translation. Full article

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by impaired social interaction and repetitive stereotyped behaviors, with pathogenic mechanisms that remain incompletely understood. The gut microbiota has emerged as a key regulator of ASD; however, its impact on hippocampal proteomic and phosphoproteomic signatures has not been fully characterized. In this study, we performed fecal microbiota transplantation (FMT) by transferring fecal samples from children with ASD and typically developing controls into antibiotic-treated mice. Gut microbiota from children with ASD induced several ASD-like behaviors in recipient mice, accompanied by aberrant activation of microglia, astrocytes, and neurons, as well as impaired neurogenesis. Phosphoproteomic profiling combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that differentially phosphorylated proteins were predominantly enriched in synapse-related pathways. ASD-derived microbiota markedly reduced synaptic density, downregulated the synaptic proteins SYP and PSD-95, and inhibited the expression of blood–brain barrier (BBB) tight junction proteins. In silico structural simulations using AlphaFold3 (AF3) and HADDOCK further supported that ASD-FMT may promote abnormal phosphorylation, potentially remodeling SHANK3 and SRRM2 conformations and weakening the binding affinity of SHANK3. Integrative proteomic and phosphoproteomic screening identified FNDC3A as a potential susceptibility-associated protein upregulated by gut microbiota from children with ASD, which was verified in mouse hippocampal tissues and plasma samples from children with ASD using Western blotting and ELISA, respectively. Mechanistically, ASD pathogenesis may be attributable not only to the dysregulation of classical ASD susceptibility genes but also to gut microbiota-driven post-translational phosphorylation remodeling of multiple protein structures. Importantly, this study established an innovative research framework that integrates in silico analyses with wet-lab experiments, yielding novel insights into ASD pathogenesis from the perspective of gut microbiota-induced alterations in the hippocampal phosphoproteome and revealing a plausible molecular mechanism underlying ASD. Full article

Tryptophan (Trp) metabolism lies at the intersection of nutrition, gut microbiota, mucosal immunology, and systemic inflammation—processes that play key roles in many gastrointestinal and extraintestinal diseases. Trp is an essential amino acid obtained through dietary intake. Beyond its role in protein synthesis, it is metabolized through three principal pathways: the kynurenine pathway, the serotonin/melatonin pathway, and microbial metabolism in the gut leading to indole and related derivatives. The kynurenine pathway represents the primary route of Trp degradation and is strongly linked to inflammatory signaling. The serotonin pathway is particularly important for gastrointestinal physiology, influencing motility, secretion, and visceral sensitivity. In parallel, microbial Trp metabolism produces metabolites that regulate epithelial barrier integrity, modulate mucosal immune responses, and contribute to communication along the gut–organ axes. Across different disease states, several recurring patterns emerge. Inflammatory conditions frequently shift Trp metabolism toward the kynurenine pathway through increased IDO1 or TDO activity, resulting in changes in kynurenine metabolites and in the kynurenine-to-tryptophan (Kyn/Trp) ratio. At the same time, reduced microbial production of indole derivatives may impair aryl hydrocarbon receptor signaling and weaken barrier-protective and immunoregulatory mechanisms. Alterations in the serotonin pathway are also associated with disturbances in gastrointestinal motility and gut–brain communication. Together, these observations highlight Trp metabolism as an important framework for understanding interactions between diet, microbiota, and host responses in health and disease. However, it is important to clarify that much of the currently available evidence remains associative or is derived primarily from preclinical models. This narrative review, based on literature retrieved from major biomedical databases (e.g., PubMed/MEDLINE, Scopus, and Web of Science), aims to provide an updated synthesis of current knowledge on Trp metabolism in disease pathophysiology. Furthermore, while we highlight potential translational applications—such as proposed biomarker development and targeted therapeutic strategies—these perspectives have been moderated to acknowledge the limited level of clinical validation established to date. Full article

Background: Population aging is accompanied by progressive immune remodeling, chronic low-grade inflammation, and increased susceptibility to neurodegenerative diseases. Although the microbiota–gut–brain axis is increasingly recognized as a regulator of neuroimmune homeostasis, mechanisms linking age-associated dysbiosis with immunosenescence, barrier dysfunction, and brain aging remain incompletely understood. This review integrates current evidence into the proposed Gut–Immune–Brain Resilience Axis (GIBRA), a systems-level model describing how microbial signaling shapes neuroimmune resilience during aging. Methods: A structured narrative review was conducted using PubMed and the Web of Science Core Collection from database inception up to July 2026. Evidence from systematic reviews, meta-analyses, consensus statements, mechanistic and translational studies, longitudinal cohorts, randomized clinical trials, and observational studies was synthesized. Results: Current evidence supports an important role for the disruption of microbial functional signaling in neuroimmune aging, while microbial taxonomy and functional profiles provide complementary levels of biological information. Reduced short-chain fatty acid production, dysregulated tryptophan metabolism, microbial translocation, endotoxin-mediated innate immune activation, and gut-conditioned adaptive immune responses promote immunosenescence, inflammaging, barrier dysfunction, and microglial priming. The proposed Double-Barrier Hypothesis links intestinal and blood–brain barrier dysfunction as complementary mechanisms underlying chronic neuroinflammation. GIBRA highlights functional microbiome endotypes, biomarkers, multi-omics, and artificial intelligence as emerging tools for precision medicine. Conclusions: GIBRA provides an integrated systems biology perspective connecting microbial signaling, immune resilience, barrier integrity, and brain resilience during aging. Prioritizing functional resilience over microbial taxonomy may improve biomarker discovery, patient stratification, and microbiome-targeted interventions for neurodegenerative disease prevention. Prospective longitudinal studies integrating multi-omics are needed to support clinical translation. Full article

Background: The dynamic advancement of pediatric hemato-oncology and intensified therapeutic protocols have significantly increased survival rates while simultaneously highlighting the challenge of long-term treatment complications. Within the cohort of adolescent and young adult (AYA) survivors, delayed neurocognitive deficits, often manifesting as the chemobrain phenotype, and psychosocial disorders constitute a particularly substantial burden. Contemporary neurogastroenterological evidence indicates a fundamental role of persistent dysbiosis and gut–brain axis dysfunction in the pathogenesis of these alterations. This review aims to critically synthesize translational evidence elucidating the impact of iatrogenic gut microbiota damage and modifiable dietary patterns on the development of long-term neurocognitive sequelae in survivors of early childhood cancer. Methods: A systematized narrative review was conducted in accordance with the SANRA guidelines by integrating data from in vivo models and observational studies. A comprehensive literature search across the PubMed, Embase, Cochrane Central, Scopus, and Web of Science databases up to June 2026 was performed utilizing the Population, Exposure, and Outcomes (PEO) framework. Results: Oncological therapies, including myeloablative conditioning and broad-spectrum antibiotic therapy, induce a microbial scar phenomenon characterized by the depletion of commensal Firmicutes in favor of resistant pathobionts. The subsequent decline in the synthesis of neuroprotective short-chain fatty acids (SCFAs) alongside the pathological activation of the kynurenine pathway disrupts central nervous system homeostasis. Translocation of lipopolysaccharides (LPSs) across the compromised intestinal barrier generates systemic inflammation recognized as inflammaging, which, in turn, stimulates neurotoxic microglial hyperreactivity. This pathophysiological cascade is accelerated by a pro-inflammatory Western diet, whereas anti-inflammatory interventions such as the MIND diet and postbiotics demonstrate measurable restorative potential. Conclusions: The pathophysiology of delayed neurotoxicity is largely a consequence of systemic neuroinflammation driven by intestinal dysbiosis. Implementing individualized dietary and microbiome-targeted strategies into survivorship care protocols constitutes a crucial direction for clinical prophylaxis. Validating their clinical efficacy in the AYA population necessitates prospective randomized controlled trials integrated with shotgun metagenomic sequencing. Full article

Pediatric disorders of gut–brain interaction (DGBIs) comprise chronic or recurrent symptom-based gastrointestinal conditions that cannot be fully explained by identifiable structural, biochemical, or organic abnormalities after appropriate clinical evaluation. The term DGBI is used throughout this review in accordance with current terminology, whereas the historical term “functional gastrointestinal disorders” (FGIDs) is retained only when referring to studies that used earlier Rome classifications. This review examines the impact of four modifiable factors—sleep, psychological stress, circadian rhythm, and diet—on their development and severity in children and adolescents. Relevant literature was identified through PubMed, with emphasis on recent pediatric studies, systematic reviews, and meta-analyses. Sleep disturbances are associated with greater abdominal pain, functional disability, and impaired daytime functioning. Stress may exacerbate symptoms through hypothalamic–pituitary–adrenal axis activation, autonomic imbalance, altered motility, and visceral hypersensitivity. Circadian disruption may affect gastrointestinal motility, barrier function, enteroendocrine signaling, and microbial rhythmicity, although pediatric evidence remains limited. Diet influences fermentation, microbiota, intestinal permeability, and symptom expression, with regular meals, adequate hydration, and appropriate fiber intake representing important initial measures. These factors interact bidirectionally through shared neuroendocrine, autonomic, immune, and microbial pathways. Clinical management should therefore adopt a biopsychosocial, multidisciplinary approach combining symptom management with modification of sleep, stress, circadian habits, and dietary patterns. Further prospective pediatric studies are needed to clarify causality and support personalized interventions. Full article

Depression (major depressive disorder, MDD) is a globally prevalent, highly disabling, and complex mental disorder whose pathogenesis has not been fully elucidated. In recent years, the role of the gut microbiota in depression via the “microbiota–gut–brain axis” (MGB axis) has attracted increasing attention. A large body of evidence indicates that the gut microbiota and its metabolites can engage in bidirectional communication with the central nervous system through three core pathways—neural, immune, and metabolic—thereby profoundly influencing the onset and progression of depression. This article reviews the specific mechanisms by which the gut microbiota affects depression through the aforementioned pathways, including regulating the balance of neurotransmitters (e.g., GABA and 5-HT), mediating neuroinflammatory responses, and adjusting the levels of metabolites such as short-chain fatty acids. This study aims to provide a theoretical basis for an in-depth understanding of the pathophysiological mechanisms of depression and the development of novel microbiota-based intervention therapeutic strategies. Full article

Background: High-altitude hypobaric hypoxia (HH) is a major environmental stressor that impairs cognitive function, yet effective and widely available therapeutics remain limited. Although Rhodiola rosea has shown neuroprotective effects, its resource scarcity restricts large-scale application. Cistanche tubulosa (Schrenk) Wight, a traditional Chinese functional food, has been increasingly used in health supplements due to its anti-fatigue, anti-dementia, and memory-enhancing properties, suggesting potential benefits against hypoxia-induced cognitive impairment. Objective: This study aimed to investigate the effects of C. tubulosa ethanol extract (CTE) on hippocampal tissue and gut microbiota upon chronic HH exposure using SPF male Sprague–Dawley (SD) rats. Methods: A total of 60 male SD rats were randomly assigned to six experimental groups (n = 10 per group): normoxic control, untreated HH model, positive control (R. rosea), and low-, medium-, high-dose CTE treatment groups. Behavioral tests (Morris water maze), hippocampal histopathology, serum and hippocampal oxidative stress markers (SOD, GSH-Px, MDA), expression of PI3K/Akt/mTOR-HIF-1α signaling pathway proteins (by immunohistochemistry), and gut microbiota composition (by 16S rRNA sequencing) were evaluated. Results: The results demonstrated that CTE significantly improved cognitive function, enhanced SOD and GSH activities, and reduced MDA levels in both hippocampus and serum. CTE also modulated the expression of PI3K/Akt/mTOR-HIF-1α pathway proteins in the hippocampus. Furthermore, CTE altered gut microbial diversity and abundance, increasing the proportion of beneficial bacteria, which may further influence hippocampal function via the gut–brain axis. Conclusion: These findings provide scientific evidence for the application of C. tubulosa as a potential health supplement for high-altitude adaptation and lay a foundation for subsequent research. Full article