Search Results (22,722)

Endothelial dysfunction is a key characteristic of many diseases, including atherosclerosis, hypertension, heart failure, stroke, cancer, acute respiratory distress syndrome (ARDS), peripheral vascular disease, coronavirus 2019 (COVID-19), and pulmonary arterial hypertension (PAH). To improve understanding of the roles of endothelial cells (ECs) in health and disease, EC-specific genome editing technologies have been developed in recent years. Therapeutic strategies that aim to restore a healthy endothelial monolayer include the inhibition of endothelial genes that cause EC injury and dysfunction and the induction or activation of endothelial genes that drive EC repair and regeneration. In this review, we describe established recombinase-mediated genetic modification technologies and emerging EC-specific genome editing technologies including viral and non-viral delivery of the CRISPR/Cas9 genome editing system, and we summarize the strengths and limitations of each technology. We then discuss possible avenues for future research, including the development of organ-specific EC genome editing technologies. In short, EC-specific genome editing technologies can be used to modulate gene expression selectively in ECs and even within a specific vascular bed and/or distinctive EC subtype, and, in doing so, greatly improve the understanding of vascular biology and help develop precision genetic medicine targeting the disease-causing vascular bed(s) to effectively treat diseases caused by vascular endothelial dysfunction. Full article

Background: Regional dietary variations in China are well-documented, but their mortality associations in local populations, particularly among individuals with type 2 diabetes (T2D) or hypertension, remain unclear. This study aimed to identify dietary clusters in Suzhou and investigate their associations with mortality. Methods: This prospective analysis included 53,269 participants aged 30–79 years from the China Kadoorie Biobank (CKB) Suzhou Wuzhong subcohort. The baseline diet was assessed via a food frequency questionnaire, and three dietary clusters were identified by K-means clustering of 10 food groups. Multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular disease (CVD), diabetes-related, and cancer mortality, stratified by baseline health status, T2D, and hypertension. Results: During follow-up, 1263 deaths occurred among healthy adults, 351 in T2D, and 2410 in hypertension. The Traditional/Preserved-Heavy cluster was characterized by lower intake frequencies across most food groups and more frequent preserved vegetable intake; the Meat-Centric cluster by relatively moderate intake frequencies and higher meat and poultry intake; and the Plant-and-Dairy-Abundant cluster by relatively abundant overall dietary intake, more frequent intake of fresh fruit, dairy products, and soybean products, and less frequent preserved vegetable intake. With the Meat-Centric cluster (cluster 2) as the reference, the Plant-and-Dairy-Abundant cluster (cluster 3) in T2D was associated with lower all-cause (HR = 0.61, 95% CI: 0.44–0.85), CVD (0.47, 0.24–0.91), and diabetes-related mortality (0.25, 0.09–0.71). BMI modified the association with all-cause mortality in T2D (p interaction = 0.033). In hypertension, cluster 1 was linked to higher all-cause (1.13, 1.03–1.23) and CVD mortality (1.17, 1.00–1.37), whereas cluster 3 was associated with a lower risk of diabetes-related mortality (0.40, 0.16–0.98). Conclusions: A dietary habit rich in fruit, dairy products, soybean products, and less frequent preserved vegetable intake was associated with lower mortality risk, particularly in T2D patients, whereas a habit with lower overall intake and more frequent preserved vegetable intake was linked to higher mortality in hypertension participants. These findings should be interpreted in light of the accompanying socioeconomic and lifestyle differences across dietary clusters. Full article

Background: The pharmacological management of type 2 diabetes mellitus has become increasingly complex due to expanding therapeutic options and the high prevalence of multimorbidity in affected patients. As a result, the risk of drug–drug and drug–disease interactions has grown significantly, with potential implications for glycemic control, safety, and treatment outcomes. Objective: This narrative review provides a comprehensive, class-based overview of clinically relevant interactions associated with antidiabetic medications, highlighting their mechanisms, clinical consequences, and practical management strategies. Methods: A targeted literature search was conducted using major medical databases to identify clinical studies, meta-analyses, pharmacovigilance reports, and evidence-based guidelines concerning interactions related to key antidiabetic drug classes. Interactions were categorized as pharmacokinetic, pharmacodynamic, or disease-related. Results: Significant variability exists across antidiabetic drug classes in terms of interaction profile and clinical relevance. Metformin presents interaction risks mainly through renal impairment or co-administration with drugs affecting lactate metabolism. Sulfonylureas and glinides are strongly associated with hypoglycemia-enhancing interactions. DPP-4 inhibitors generally exhibit a low interaction burden, whereas GLP-1 receptor agonists may interact through delayed gastric emptying. SGLT2 inhibitors require caution in patients with diuretics or conditions predisposing them to dehydration or ketoacidosis. Insulin remains highly sensitive to pharmacodynamic interactions with a broad spectrum of therapies. Underlying renal, hepatic, and cardiovascular conditions further modify the interaction risk. Conclusions: Understanding class-specific interaction profiles is essential for personalized and safe diabetes management. Careful medication review, close metabolic monitoring, and individualized dose adjustments can mitigate the risk of harmful interactions. Further research is needed to elucidate interactions in populations with advanced multimorbidity and polypharmacy. Full article

Secondary hyperparathyroidism (SHPT) is a major component of chronic kidney disease–mineral and bone disorder (CKD-MBD), reflecting progressive disturbances in mineral metabolism, endocrine signaling, skeletal remodeling, and parathyroid-gland biology. Traditionally, preoperative parathyroid hormone (PTH) has been used primarily as a biochemical threshold for surgical referral. However, persistent PTH elevation in advanced CKD-related SHPT may reflect more than isolated endocrine activity; available evidence suggests it integrates parathyroid-gland remodeling, receptor resistance, skeletal turnover, treatment refractoriness, and systemic CKD-MBD severity. This review summarizes key molecular and cellular mechanisms of progressive SHPT, including diffuse-to-nodular hyperplastic transition, downregulation of calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) signaling, disruption of the fibroblast growth factor 23 (FGF23)–Klotho axis, and activation of transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) proliferative pathways. Building on this mechanistic framework, we discuss how persistent PTH elevation has been linked to glandular remodeling, resistance to calcimimetic and vitamin D therapy, high-turnover renal osteodystrophy, hungry bone syndrome, altered intraoperative PTH kinetics, postoperative endocrine–skeletal remodeling, and long-term recurrence. Severe SHPT is also increasingly recognized as a systemic CKD-MBD phenotype associated with vascular calcification, cardiovascular risk, metabolic instability, and impaired quality of life. Within this framework, preoperative PTH is best interpreted as an integrated biomarker within a broader assessment of glandular remodeling, skeletal metabolic activity, endocrine resistance, and systemic CKD-MBD biology, rather than as an isolated biochemical threshold. Full article

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction is increasingly recognized as a key contributor to a broad spectrum of human diseases beyond classical cystic fibrosis (CF). CFTR is a cAMP-regulated chloride and bicarbonate ion channel expressed in both epithelial and non-epithelial tissues, where it regulates ion homeostasis, mucosal hydration, and cellular signaling. Both inherited CFTR mutations and acquired dysfunction resulting from environmental or inflammatory factors can disrupt these physiological processes and drive disease progression. Current evidence linking CFTR dysregulation to respiratory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, and HIV-associated airway disease, as well as cardiovascular, renal, neurological diseases, and cancer, is comprehensively discussed. Mechanistically, impaired CFTR function promotes oxidative stress, chronic inflammation, epithelial barrier dysfunction, altered mucociliary clearance, and dysregulation of signaling pathways, including NF-κB, TGF-β, PI3K/Akt, MAPK, and Wnt/β-catenin. In the context of HIV infection and cigarette smoke exposure, CFTR suppression is mediated in part by TGF-β signaling and miRNA-dependent mechanisms, resulting in compromised airway defense and increased susceptibility to pulmonary complications. Recent studies further demonstrate that CFTR dysregulation alters the expression of genes involved in fibrosis, inflammation, angiogenesis, and epithelial–mesenchymal transition (EMT). Notably, CFTR may act as either a tumor suppressor or a context-dependent oncogene, depending on tissue type and signaling milieu, highlighting its complex role in cancer biology. Advances in CFTR-targeted therapies, including potentiators, correctors, gene therapy, and combination approaches, have markedly improved outcomes in CF and may offer therapeutic potential for diseases associated with acquired CFTR dysfunction. We summarize the systemic consequences of CFTR dysregulation and the need for further mechanistic and translational research to clarify its role across diverse human diseases. Full article

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality globally among older adults. Similar to humans, age-related declines in cardiac function are observed in C57BL/6 mice. Angiotensin-converting enzyme 2 (ACE2), a key component of the renin–angiotensin system (RAS), counteracts detrimental RAS effects by converting angiotensin II (Ang II) to angiotensin-(1-7) (Ang-(1-7)), thereby playing a critical role in mitigating CVD pathogenesis. Here, we utilized transgenic K18-hACE2 mice to investigate the protective effects of ACE2 against cardiac aging. Histological and morphometric analyses revealed significant reductions in heart weight and improvements in cardiac structure in K18-hACE2 mice compared to wild-type controls. Furthermore, aged C57BL/6 mice exhibited progressive cardiac aging phenotypes, including mitochondrial dysfunction, telomere shortening, and immune dysregulation—all of which were significantly attenuated in K18-hACE2 mice. These findings demonstrate the protective role of ACE2 in cardiac aging and highlight its potential as a therapeutic target for anti-aging interventions. Full article

Background: Myocardial fibrosis is an important pathological feature of hypertrophic cardiomyopathy (HCM) and is associated with ventricular arrhythmias, disease progression, and adverse clinical outcomes. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) is the reference non-invasive technique for myocardial fibrosis assessment; however, its availability may be limited. Global longitudinal strain (GLS) derived from transthoracic echocardiography (TTE) has emerged as a sensitive marker of myocardial dysfunction and may provide complementary information regarding myocardial involvement. Aim: The aim of our study was to evaluate the diagnostic value of transthoracic echocardiography (TTE) with 2D global longitudinal strain (GLS) to detect the degree of myocardial fibrosis (LGE) in patients with LV hypertrophy (LVH). Methods: A total of 95 consecutive patients referred for cardiovascular magnetic resonance (CMR) because of suspected hypertrophic cardiomyopathy or left ventricular hypertrophy were screened for eligibility. After applying exclusion criteria and excluding patients with alternative diagnoses or inadequate image quality, 83 patients were included in the final analysis. All the participants underwent both CMR and transthoracic echocardiography with GLS assessment. Results: The final study population included 83 patients (57.5 ± 13 years; 66% males). CMR confirmed HCM in 58 (70%) patients, including 23 with left ventricular outflow tract obstruction (LVOTO). The remaining patients demonstrated varying degrees of left ventricular hypertrophy that did not fulfill established diagnostic criteria for hypertrophic cardiomyopathy. Cardiovascular magnetic resonance studies (58 cases; 69%) showed a non-ischemic LGE in LV (23% of segments with LGE). GLS in patients with LGE was significantly lower than those without LGE (−13.9 ± 3.6 vs. −15.9 ± 2.7%, p = 0.01). The mean GLS was −14.52 ± 3.5% and showed a moderate positive correlation with the extent of myocardial fibrosis (LGE%LV; r = 0.45, p < 0.01). This relationship remained significant in multivariable regression analysis (standardized coefficient = 0.683; p < 0.05). Moreover, the transthoracic echocardiography GLS showed a significant association for LV LGE (−14.3%; AUC 0.658; p = 0.01, sensitivity 39%, specificity 90%) with a better diagnostic performance for LGE in more than four LV segments (−12.1%; AUC 0.867; p < 0.001, sensitivity 72%, specificity 87%). Conclusions: GLS was independently associated with myocardial fibrotic burden assessed by CMR. Although it cannot replace CMR for tissue characterization, GLS may provide adjunctive information and may help identify patients with greater fibrotic burden. Prospective studies are needed to validate its clinical utility. Full article

Background/Objectives: Lipoprotein(a) [Lp(a)] is an established risk-enhancing biomarker for atherosclerotic cardiovascular disease (ASCVD) and is increasingly incorporated into preventive risk assessment. However, whether Lp(a) predicts long-term cardiometabolic disease (CMD) beyond its associations with lipid parameters in apparently healthy women remains unclear. Methods: We retrospectively analyzed 559 women (median age 41 [36–46] years) who underwent comprehensive health check-ups with baseline Lp(a) measurements. After excluding those with baseline CMD, ASCVD, or insufficient follow-up, 387 women formed the primary longitudinal cohort. Participants were stratified by Lp(a) level (<50 vs. ≥50 mg/dL). Incident composite CMD, defined as new-onset hypertension, diabetes mellitus, or dyslipidemia, was assessed using Kaplan–Meier analysis, Cox proportional hazards models, and sensitivity analyses treating Lp(a) as a continuous variable and restricting the analysis to participants with ≥10 years of follow-up. Results: At baseline, elevated Lp(a) (≥50 mg/dL) was associated with higher total cholesterol and LDL-C and a greater prevalence of dyslipidemia, with a modest Lp(a)–LDL-C correlation (ρ = 0.24, p < 0.001). Over a median follow-up of 12.6 years, CMD incidence did not differ between Lp(a) groups (33.3% vs. 35.3%, p = 0.907). Lp(a) was not associated with incident CMD in multivariable Cox models (adjusted HR 0.81, 95% CI 0.49–1.34), with consistent findings in the ≥10-year follow-up subgroup (n = 224) and in continuous-variable sensitivity analyses. Conclusions: In apparently healthy women, elevated Lp(a) reflects an adverse baseline lipid phenotype but does not independently predict long-term incident CMD. These findings suggest that the clinical utility of Lp(a) may be context-dependent, with its predictive value primarily limited to ASCVD risk assessment rather than broader cardiometabolic risk prediction in this population. Full article

Background/Objectives: Chronic kidney disease (CKD) is characterized by accelerated aging and functional decline. Serum α-Klotho levels, an anti-aging biomarker predominantly associated with renal function, have emerged as potential indicators of biological aging and cardiovascular risk. To investigate the association between serum α-Klotho levels and habitual physical activity in hemodialysis patients. Methods: This study combined (1) a prospective case analysis of high-intensity interval training (HIIT) in a hemodialysis patient and (2) a cross-sectional analysis of 24 hemodialysis patients and 18 healthy controls. Serum α-Klotho levels were measured using ELISA, and their association with habitual physical activity was evaluated. Results: Serum α-Klotho levels were significantly lower in hemodialysis patients than in healthy controls (p < 0.001). In hemodialysis patients, physical activity was moderately correlated with serum α-Klotho levels (r = 0.52, p = 0.02), whereas no significant association was observed in healthy controls. The case analysis demonstrated marked improvement in physical function following HIIT. These findings suggest that serum α-Klotho levels may be associated with physical activity status in hemodialysis patients. Conclusions: Serum α-Klotho levels were associated with habitual physical activity in hemodialysis patients and may represent a potential molecular indicator related to physical function and rehabilitation status. These findings support further investigation of biomarker-informed approaches in renal rehabilitation. Full article

Background/Objectives: To evaluate the associations and concurrent validity between baseline functional and morphofunctional assessments in patients with cardiovascular disease participating in a Phase II cardiac rehabilitation program, as a basis for informing individualized exercise prescription. Methods: We conducted an observational retrospective cross-sectional study of patients enrolled in a Phase II outpatient cardiac rehabilitation program (January 2021–December 2023, Málaga). Functional assessments included handgrip strength (HGS), isometric biceps and quadriceps dynamometry, and direct assessment of 20-repetition maximum (20RM) through dynamic resistance exercises using external loads (defined as the maximum load allowing approximately 20 repetitions to near muscular fatigue). Aerobic capacity was evaluated using the 6-min walk test (6 MWT) and a modified Bruce exercise stress test with estimated METs. Morphofunctional assessment included vector bioimpedance analysis (phase angle [PhA], fat-free mass [FFM], body cell mass [BCM]) and rectus femoris ultrasound (cross-sectional area [RF-CSA] and contracted diameter [RF-CON]). Correlation and linear regression analyses were performed. Results: The sample included 223 participants (78.0% male; age 57.7 ± 8.6 years). HGSmax correlated strongly with 20RM biceps (r = 0.89) and moderately with quadriceps (r = 0.72). 6 MWT distance and speed correlated with ergometry-derived METs (r = 0.38–0.40; p < 0.001), whereas Borg ratings correlated inversely with METs and exercise time (r = −0.32 to −0.34; p < 0.001). PhA, BCM, FFM, and rectus femoris ultrasound measures correlated with both strength and aerobic outcomes (ρ ≈ 0.33–0.50; all p < 0.001). In regression analyses, HGSmax was the main predictor of 20RM biceps (R² = 0.792) and showed moderate predictive capacity for quadriceps performance (R² = 0.521). The MET model demonstrated limited explanatory capacity (R² = 0.288). Conclusions: The integration of simple, accessible, and reproducible tools such as HGS and the 6 MWT with morphofunctional parameters may provide a pragmatic approach to support individualized exercise prescription in cardiac rehabilitation. While stronger associations were observed for upper-limb resistance performance, the predictive capacity for lower-limb strength and aerobic exercise intensity was more moderate and should be interpreted cautiously. These findings support the potential clinical utility of combining functional and morphofunctional assessments in routine cardiac rehabilitation practice. Full article

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a highly prevalent multisystem disorder and is strongly associated with increased cardiovascular risk. Cardiovascular diseases represent the leading cause of mortality in this population. As the hepatic manifestation of systemic metabolic dysfunction, MASLD is initiated by excess lipid accumulation driven by increased dietary fatty acid intake and accelerated de novo lipogenesis. This triglyceride overload induces lipotoxicity, triggering hepatocellular injury, immune activation, and mitochondrial dysfunction. Excessive mitochondrial reactive oxygen species (ROS) generation acts as a critical second hit, promoting inflammatory cytokine production and disease progression. Beyond lipid dysregulation, impaired hepatic insulin signaling leads to hyperglycemia and compensatory hyperinsulinemia, further stimulating lipogenesis and reinforcing a self-perpetuating metabolic cycle. Persistent ROS production overwhelms antioxidant defenses and depletes hepatic glutathione (GSH), resulting in systemic redox imbalance. These disturbances extend beyond the liver, contributing to atherogenic dyslipidemia and chronic inflammation. In parallel, gut dysbiosis and increased intestinal permeability amplify immune activation. Reduced circulating GSH further weakens systemic antioxidant capacity; oxidative stress may represent a central mechanistic link between MASLD and CVD. In concert with metabolic and inflammatory mediators, ROS disrupt pathways governing vascular and myocardial homeostasis, leading to coronary atherosclerosis, microvascular dysfunction, left ventricular remodeling, hypertrophy, and impaired relaxation. Clinically, this translates into an increased burden of coronary artery disease and heart failure, particularly heart failure with preserved ejection fraction. Given this integrated pathophysiology, early identification of subclinical cardiovascular involvement is essential. We highlight emerging biomarkers, advocate for multidisciplinary screening strategies, and discuss integrated pharmacological approaches targeting shared metabolic pathways. Recognizing MASLD as a cardiovascular risk amplifier is critical for improving risk stratification and enabling the development of effective, co-targeted therapeutic strategies. Full article

Disruption of cholesterol homeostasis is closely associated with hypercholesterolemia, dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), and metabolic disorders such as metabolic dysfunction-associated fatty liver disease (MAFLD). Intestinal and hepatic cholesterol absorption are central to maintaining systemic cholesterol balance, with Niemann–Pick C1-Like 1 (NPC1L1) acting as a key transporter that mediates cholesterol uptake in enterocytes and hepatocytes. Aberrant NPC1L1 expression or activity promotes excessive cholesterol accumulation in both plasma and liver, thereby contributing to dyslipidemia and hepatic steatosis. Consequently, NPC1L1 has emerged as an important therapeutic target for reducing cholesterol absorption and improving lipid homeostasis. Although ezetimibe is currently the only clinically approved NPC1L1 inhibitor, its limited efficacy as monotherapy highlights the need for alternative or complementary therapeutic strategies. Growing evidence indicates that natural phytochemicals, particularly polyphenols and flavonoids, can modulate NPC1L1 at both transcriptional and functional levels. These compounds not only suppress intestinal cholesterol absorption but also attenuate hepatic lipid accumulation, ultimately improving circulating lipid profiles. This review summarizes recent advances in understanding the role of NPC1L1 in cholesterol metabolism and highlights the emerging therapeutic potential of phytochemicals as novel complementary approaches for the prevention and treatment of lipid metabolic disorders. Full article

Background: Myocardial infarction triggers a complex remodeling process involving inflammation, hypertrophy, fibrosis, and electrical adaptation, ultimately predisposing the heart to failure. Krüppel-like factors (KLFs) are transcriptional regulators implicated in cardiovascular development and disease; however, a comprehensive temporal characterization of their coordinated activity during post-injury remodeling remains lacking. Objective: To define the temporal orchestration of the KLF family during myocardial injury and hypertrophy, and to integrate these dynamics within regulatory networks associated with cardiac remodeling. Methods: Myocardial injury was induced in rats using intraperitoneal isoproterenol. Left ventricular tissue was collected over a 21-day period. Cardiac morphometry, histology, immunohistochemistry, and quantitative gene expression analyses were performed to evaluate structural and transcriptional changes. Publicly available human cardiac and fibroblast datasets were analyzed for translational comparison, and protein–protein interaction networks were constructed to identify functional associations. Results: Isoproterenol treatment induced progressive hypertrophy, structural disorganization, and sustained fibrotic remodeling. KLFs displayed coordinated, phase-specific regulation, characterized by early activation of inflammation-associated members, intermediate engagement of factors linked to transforming growth factor signaling and hypertrophy modulation, and late induction of regulators associated with apoptosis and scar formation. These temporal patterns paralleled changes in inflammatory mediators, cardiac transcription factors, and genes involved in electrical and calcium handling pathways. Human expression analyses supported tissue-specific specialization of key KLFs. Conclusions: KLFs exhibit a coordinated and temporally structured regulatory program during myocardial remodeling, functioning as a transcriptional network that integrates inflammation, fibrosis, hypertrophy, and electrical adaptation. These findings position KLFs as key regulatory nodes in cardiac remodeling and potential targets for therapeutic intervention. Full article

Background/Objectives: Exocrine pancreatic insufficiency (EPI) is increasingly recognized in patients with diabetes; however, its clinical correlates remain poorly defined. This study aimed to determine the prevalence and clinical characteristics of EPI in patients with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) and to evaluate its associations with diabetes-related complications and insulin therapy. Methods: A total of 200 patients with diabetes were screened, and 182 who met the inclusion criteria were included in the final analysis. EPI was diagnosed using fecal elastase-1 (FE-1). Clinical, biochemical, and complication-related data were collected. Factors associated with EPI were evaluated using univariate and multivariate logistic regression analyses. Among patients with T2DM, an inverse probability of treatment weighting–average treatment effect on the treated (IPTW-ATT) model was constructed to evaluate the association between insulin therapy and EPI. Propensity scores were estimated using baseline demographic and clinical covariates, and covariate balance after weighting was assessed using standardized mean differences (SMDs). Results: Exocrine pancreatic insufficiency was detected in 18.1% of patients, with prevalences of 21.2% in T1DM and 17.4% in T2DM. Cardiovascular disease was the only variable independently associated with EPI in multivariate analysis (OR = 3.25; 95% CI: 1.12–6.75; p = 0.028. Among patients with T2DM, insulin therapy was significantly associated with EPI in both unadjusted and IPTW-ATT analyses (weighted OR = 10.76; 95% CI: 1.85–62.76; p = 0.008) with a wide confidence interval reflecting sparse data. Cardiovascular disease also remained significantly associated with EPI in the weighted model (OR = 3.52; 95% CI: 1.22–10.15; p = 0.020). Conclusions: Exocrine pancreatic insufficiency is a clinically relevant condition in diabetes and shows a significant cross-sectional association with cardiovascular disease. In T2DM, insulin therapy was associated with a higher prevalence of EPI, although confounding by indication cannot be excluded. These findings suggest that evaluation of exocrine pancreatic function may be considered in high-risk diabetic subgroups, pending confirmation in prospective longitudinal studies. Full article

Folate (vitamin B9) is central to one-carbon metabolism, supporting nucleotide biosynthesis, methylation homeostasis, and epigenetic regulation. The gut microbiome both produces and consumes folate, creating a bidirectional axis influencing host health and disease. We systematically reviewed 159 original studies from MEDLINE, Google Scholar, Embase, and Scopus (inception through January 2026) examining enteric microbiota–folate interactions, with intervention evidence graded using the Oxford Centre for Evidence-Based Medicine 2011 framework. Only a minority of gut bacteria possess complete folate biosynthetic pathways; most depend on cross-feeding from prototrophic taxa including Bifidobacterium, Lactobacillus, and Streptococcus. Altered microbial folate metabolism was associated with metabolic, gastrointestinal, oncologic, neuropsychiatric, cardiovascular, immunologic, and reproductive disorders through convergent mechanisms of disrupted methylation, genomic instability, and immune dysregulation. Probiotic interventions achieved the strongest evidence, supported by multiple human controlled and observational trials and animal models. The evidence for prebiotic, dietary, and folate supplementation interventions was moderate due to the predominant animal models and in vitro data. Overall, the predominant associational and observational evidence base is insufficient to establish causal relationships, underscoring the need for adequately powered human randomized controlled trials with folate-specific endpoints, multi-omics integration, and precision approaches matching folate form and dose to individual microbiome and host genetic profiles. Full article