Search Results (358)

Cardiac amyloidosis is a rare and progressive condition characterized by the extracellular deposition of amyloid fibrils in multiple organs. Wild-type transthyretin amyloidosis (ATTR-wt) is the most common type affecting subjects above 60 years old. Recent and growing evidence suggests a potential link between GM and cardiac amyloidosis. In this scenario, the aim of the present study is to characterize the gut microbiota (GM), related metabolites and inflammatory biomarkers in ATTR-wt patients. In the ATTR patients we identified Prevotella_9 as the core OTUs (Operational Taxonomic Unit) of this group, alongside Prevotella 7, Prevotellaceae_UCG-003 and Prevotellaceae_NK3B31. In addition, there were increased levels of long fatty acids, including tetradecanoic, hexadecanoic and octadecanoic acids, in the ATTR group. The data obtained suggest that ATTR patients have an altered gut microbiota that could be used as a potential biomarker in metabolic and cardiovascular diseases, as well as a potential predictor of adverse prognosis in ATTR patients. In addition, the intestinal dysbiosis in ATTR patients could be associated with low-grade endotoxemia promoting a pro-inflammatory state due to the translocation of bacterial components, such as LPS (lipopolysaccharide), into blood circulation. Full article

Growing evidence implicates neuroinflammation, gut-derived endotoxemia, and dysregulated lipid metabolism in the pathogenesis of Parkinson’s disease (PD). However, the relationships among circulating lipopolysaccharide (LPS), LPS-handling proteins, systemic inflammatory activation, and lipid fractions remain insufficiently characterized. The aim of this study was to compare LPS levels, LPS-related inflammatory mediators, and plasma lipid parameters between PD patients and matched controls, and to explore correlations among these biomarkers. Twenty PD patients and twenty matched controls underwent fasting venous sampling. Circulating LPS, lipopolysaccharide binding protein (LBP), soluble cluster of differentiation 14 (sCD14), high-sensitivity C-reactive protein (hsCRP), and phospholipid transfer protein (PLTP) were quantified via LAL assay and ELISAs. Serum cholesterol, HDL cholesterol (HDL-C), phospholipids (PLs), HDL-PLs and triacylglycerols (TAGs) were assessed using validated biochemical techniques. LPS concentrations did not differ between groups. However, PD patients showed elevated sCD14 and hsCRP levels, reduced LBP, and increased PLTP. Lipid profiling revealed lower total cholesterol and reduced HDL-associated cholesterol and phospholipids in PD, while TAG levels remained unchanged. Correlation analyses indicated coordinated associations between inflammatory markers and lipid fractions, with distinct interaction patterns in PD compared with controls. These findings support a mechanistic interplay among endotoxemia, innate immune activation, and lipid dysregulation in the pathophysiology of PD. Full article

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as potent modulators of immune responses during sepsis, yet their roles remain complex, alternating between protective and permissive depending on timing, tissue compartment, and inflammatory context. This review presents a historical assessment of VIP and PACAP in sepsis research, highlighting the evolution of conceptual advances across five decades. Starting in the 1980s, early studies revealed that VIP levels rise during endotoxemia and correlated with hypotension and mortality, suggesting a deleterious role. By the 1990s, research pivoted toward understanding gut-derived VIP and its interaction with nitric oxide, culminating in the classification of VIP and PACAP as “macrophage deactivating factors” that downregulate TNFα and IL-6. The 2000s further clarified their cell-specific actions through VPAC1/2 and PAC1 receptors, showing anti-inflammatory effects on both innate and adaptive immune cells, while illuminating delivery challenges overcome by liposomal encapsulation. The 2010s expanded this narrative by dissecting receptor dynamics, gut barrier regulation, and VIP’s role in neuroimmune crosstalk and thrombo-inflammation. Most recently, studies in the 2020s provide a nuanced view of how VIP suppresses inflammatory damage but also enables pathogen persistence during live bacterial infection, implicating VIP signaling in trade-offs between tolerance and clearance. Across this chronological framework, VIP and PACAP have oscillated between friend, foe, and frenemy, underscoring the importance of context in leveraging their therapeutic potential in sepsis. Full article

The human gut microbiota represents a complex and dynamic ecosystem of trillions of microorganisms that play a fundamental role in maintaining physiological homeostasis, regulating metabolism, and modulating the immune system. This narrative review explores the biochemical intricacies of the gut microbiome, focusing on the dominant phyla (Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Verrucomicrobia, Fusobacteria) and their specific contributions to host health. A critical emphasis is placed on the metabolic outputs of these microorganisms, such as short-chain fatty acids (SCFAs) like butyrate, which serve as vital energy sources and anti-inflammatory signaling molecules. Conversely, the review examines how dysbiosis, the disruption of microbial balance, is mechanistically linked to the pathogenesis of diverse conditions, including obesity, diabetes mellitus, inflammatory bowel disease (IBD), and gout. Furthermore, it highlights the profound impact of dietary interventions on microbial architecture, notably, how non-digestible carbohydrates promote beneficial taxa and eubiosis, while high-fat and high-sugar diets drive metabolic endotoxemia and systemic inflammation. By synthesizing current knowledge on microbial biotransformations of proteins and polyphenols, this work underscores the bidirectional relationship between nutrition and the microbiome. Ultimately, understanding these biochemical interactions is essential for developing targeted probiotic, prebiotic, and nutritional strategies to prevent and manage chronic metabolic and inflammatory disorders. Full article

Adolescence is a metabolically vulnerable period, during which rapid physiological maturation coincides with the dynamic remodelling of the gut microbiome. This narrative review summarises evidence from 2015 to 2025 to clarify how disturbances to the gut–liver axis driven by dysbiosis contribute to the development and progression of non-alcoholic fatty liver disease (NAFLD) in young people. Based on a systematic search of the databases PubMed, Scopus and Web of Science, we outline the basis of bidirectional communication between the gut and liver and emphasise how microbial imbalance alters the handling of lipids in the liver by enhancing de novo lipogenesis, impairing fatty acid oxidation and disrupting AMPK signalling and mitochondrial function. Consistent findings from clinical and experimental studies show that adolescents with NAFLD exhibit reduced microbial diversity, the enrichment of ethanol- and LPS-producing taxa, and altered short-chain fatty acid profiles. Each of these is associated with hepatic inflammation and metabolic reprogramming. Microbial molecules, including LPS, secondary bile acids and branched-chain amino acid metabolites, activate TLR4–NF-κB pathways, promote Kupffer cell activation and intensify oxidative stress. These mechanisms intersect with factors specific to adolescence, such as increased adiposity, hormonal shifts and diet-induced metabolic strain. Dietary patterns emerge as key modulators of these processes. Westernised diets promote dysbiosis and endotoxemia, whereas Mediterranean, fibre-rich and plant-based diets enhance SCFA production, strengthen epithelial integrity and modulate adiponectin-dependent hepatic metabolism. Micronutrient-sensitive epigenetic regulation, particularly that involving folate, choline and polyphenols, also plays a role in shaping lipid homeostasis and inflammatory tone. We also highlight emerging evidence that the activation of cytoprotective pathways, especially Nrf2, is dependent on lifestyle factors and links antioxidant-rich functional foods and physical activity to improved mitochondrial resilience and microbiome stability. We evaluate therapies targeting the microbiome, including probiotics, prebiotics, synbiotics and postbiotics, which reduce endotoxemia, restore microbial balance and complement dietary strategies. Thus, these findings emphasise the importance of age-specific, mechanistically informed interventions that integrate diet quality, microbial ecology, and the molecular pathways that govern metabolic health in adolescents with NAFLD. Full article

Background: Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasingly recognized as a thromboinflammatory disorder involving coagulation, innate immunity, endothelial dysfunction, and vascular homeostasis. Emerging evidence suggests that gut microbiome-related inflammatory and metabolic signals may influence pathways potentially relevant to VTE through intestinal barrier dysfunction, microbial translocation, and microbiome-derived metabolites. This review critically examines the direct and indirect evidence relating gut dysbiosis to mechanisms potentially relevant to venous thrombogenesis. Methods: A structured literature search of PubMed, Scopus, and Web of Science was conducted from database inception to February 2026. Observational, translational, experimental, preclinical, and selected genetic studies were narratively synthesized across heterogeneous evidence types. Results: Available evidence suggests that intestinal barrier dysfunction and microbial translocation may increase systemic exposure to lipopolysaccharide and other microbial products, potentially contributing to inflammatory signaling and procoagulant responses. Proposed downstream effects include tissue factor (TF) activation, platelet reactivity, neutrophil extracellular traps (NETs) formation, complement signaling, endothelial perturbation, and impaired balance of anticoagulant and fibrinolytic pathways. Microbiome-derived metabolites, including trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAGln), bile acids, and short-chain fatty acids (SCFAs), have been linked, mainly in experimental or non-VTE settings, to thrombosis-related biology. However, most evidence remains indirect, associative, or experimental, whereas direct human VTE-specific evidence is limited and heterogeneous. Conclusions: The gut microbiome–VTE axis is biologically plausible and supported mainly by mechanistic and indirect evidence, but current data are insufficient to support strong causal conclusions. Further longitudinal, well-phenotyped, mechanistically informed studies are needed to determine whether microbiome-related pathways have measurable clinical relevance in human VTE. Full article

Sepsis is a life-threatening syndrome driven by dysregulated immune activation and multi-organ dysfunction, with limited effective therapies. Oxylipins are endogenous lipid mediators that promote the resolution of inflammation and tissue repair, yet their therapeutic potential in systemic inflammatory diseases remains incompletely understood. In this study, we evaluated the effects of two oxylipins, 10-epi-Protectin DX (10-epi-PDX) and Resolvin D5_{n-3 DPA} (RvD5_{n-3 DPA}), in a lipopolysaccharide (LPS)-induced murine endotoxemia model. Given that this model recapitulates key features of systemic inflammation and multi-organ injury relevant to sepsis-associated conditions, oxylipin effects were assessed across major organs implicated in systemic inflammatory pathology. Administration of either oxylipin significantly reduced systemic tissue injury and inflammatory damage in the lungs, kidneys, and liver. These protective effects were accompanied by suppression of inflammatory responses and marked improvements in histopathological outcomes. These findings indicate that 10-epi-PDX and RvD5_{n-3 DPA} possess organ-protective, anti-inflammatory properties in endotoxemia and support further investigation of their potential as therapeutic candidates for limiting systemic inflammatory injury. Full article

Open-heart surgery with cardiopulmonary bypass (CPB) is a high-risk procedure with significant morbidity and mortality. CPB, tissue injury, blood loss, endotoxemia and ischemia–reperfusion injury induce a pronounced systemic inflammatory response, leading to endothelial glycocalyx (EG) damage and vascular endothelial dysfunction. Consequently, immune cells, reactive oxygen species, and enzymes gain free access to vascular endothelial cells, resulting in their dysfunction and enhancing inflammation, vascular permeability, and microvascular impairment. EG degradation is most commonly assessed by measuring the circulating levels of its degradation products. Additionally, CPB triggers an early inflammatory response that is characterized by the secretion of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor alpha, and IL-18, which play roles in initiating the process of EG injury. EG damage is further propagated by the sustained release of cytokines, inhibiting the regeneration of the glycocalyx layer. Heparanase and matrix metalloproteinases are enzymatic pathways involved in cytokine-mediated EG degradation after cardiac surgery, and the balance between the pro- and anti-inflammatory cytokines determines the magnitude and duration of the inflammatory response and EG impairment, which correlates with adverse clinical outcomes, including myocardial dysfunction, acute lung and kidney injury, neurological complications, and prolonged need for intensive care. Thus, identifying patients with an exaggerated cytokine response could potentially provide more personalized therapy based on the circulating biomarkers of EG shedding, and cytokine-directed preservation of EG represents a promising therapeutic strategy in vascular dysfunction prevention during and after open-heart surgery. In this review, we summarize the current knowledge on cytokine-mediated EG impairment following open-heart surgery with CPB. Full article

Increased intestinal permeability has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but its relationship with liver fibrosis independent of metabolic risk factors remains unclear. The aim of this study was to investigate the relationship between markers of gut-derived immune activation and liver fibrosis in individuals with metabolic disease. We enrolled 139 adults (48.8 ± 11 years; BMI 33.7 ± 9.5 kg/m²; 50% type 2 diabetes); liver steatosis and fibrosis were estimated using the Hepatic Steatosis Index (HSI) and Fibrotic NASH Index (FNI); liver biopsies were available in a bariatric subgroup. Plasma soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) levels were measured by ELISA kits, and the LBP/sCD14 ratio was calculated. MASLD was present in 78% of participants; in these individuals, sCD14 levels correlated with HSI and FNI (both p < 0.01). In multivariable analysis adjusting for age, sex, BMI, waist circumference, and type 2 diabetes, sCD14 was independently associated with advanced fibrosis (OR: 3.16, 95% CI 1.32–7.55; p = 0.010). This association was confirmed by histology (p = 0.02). Overall, these findings point to a link between gut-derived immune activation and fibrotic burden in MASLD and provide insight into the pathophysiological relevance of the gut–liver axis in metabolic disease. Full article

Microbiome-targeted interventions have shown promise for metabolic health, yet clinical evidence remains inconsistent, particularly across stages of metabolic disease. This study evaluated the metabolic effects, safety, and tolerability of EDC-HHA01, a microbiome-informed, non-pharmacologic intervention, in adults with prediabetes (PD) or Type 2 Diabetes (T2DM). In a randomized, double-blind, placebo-controlled clinical trial, participants received EDC-HHA01 or placebo for six months. The study was adequately powered (≥80%) for the primary endpoint. Outcomes included changes in glycated hemoglobin (HbA1c), indices of insulin resistance, markers of metabolic endotoxemia, safety-related laboratory parameters, and exploratory patient-reported measures. Analyses were stratified by metabolic status and background metformin use. In participants with PD, EDC-HHA01 supplementation was associated with a statistically and clinically meaningful reduction in HbA1c compared with placebo, supported by concordant improvements in fasting insulin, insulin resistance indices, and reductions in endotoxemia markers. In participants with T2DM, changes were directionally similar but attenuated and did not reach statistical significance. The intervention was well tolerated, with no serious adverse events, high adherence, and no clinically relevant adverse changes in renal or lipid parameters. Exploratory patient-reported outcomes indicated favorable acceptability but were not interpreted as efficacy endpoints. EDC-HHA01 was associated with biologically coherent, stage-dependent metabolic effects, most evident in PD. These findings support further investigation of microbiome-informed strategies as metabolic support in early-stage dysregulation. Full article

Background: Mechanistic evidence increasingly implicates fructose exposures as contributors to the development and exacerbation of asthma and other atopic diseases. Proposed mechanisms include gut dysbiosis, impaired epithelial barrier integrity in the gut and airways, metabolic endotoxemia, and amplification of type 2 immune responses. However, epidemiologic findings linking fructose intake with asthma and atopic disorders remain heterogeneous. Objective: To conduct a review of epidemiologic studies evaluating associations between dietary fructose-containing exposures and atopic outcomes in pediatric populations. Methods: A systematic search of PubMed and Embase identified cohort, case-control, cross-sectional, and randomized feeding studies assessing fructose exposure in relation to asthma and atopic outcomes in pediatric populations. Eligibility screening, data extraction, and risk-of-bias assessment were conducted by one reviewer and confirmed by the other. Results: Seventeen epidemiologic studies met criteria. Multiple cohorts (e.g., BRISA, PIAMA) reported modest to moderate associations between higher sugar-sweetened beverage (SSB) intake and pediatric asthma or “asthma traits.” Cross-sectional analyses from NHANES and the National Children’s Study showed stronger associations, with greater fructose exposures linked to two- to five-fold higher odds of asthma. High fructose beverage consumption demonstrated the most consistent positive associations. Large ISAAC-based studies reported largely null findings, reflecting broad dietary exposure categories and limited specificity for fructose-rich beverages. Evidence for rhinitis, eczema, and sensitization was directionally consistent. Conclusions: Despite heterogeneity, the convergence of mechanistic plausibility with epidemiologic signals supports a potential contributory role of high fructose exposure in pediatric atopic disease. More rigorous longitudinal studies with biomarker-based exposure assessment are needed to refine causal inference. Full article

Background: Altered gut microbiota and gut-derived inflammation impair glucose regulation and promote metabolic endotoxemia, yet evidence on probiotic effects across combined glycaemic, inflammatory and short-chain fatty acid (SCFA) outcomes remains limited. This study investigated the effects of a 12-week multi-species probiotic on glucose homeostasis, incretin hormones, inflammatory biomarkers and circulating SCFAs in adults with subthreshold depression. Methods: In a 12-week double-blind, randomised, placebo-controlled trial, 39 adults with subthreshold depression were allocated to either a probiotic supplement containing Limosilactobacillus fermentum LF16, Lacticaseibacillus rhamnosus LR06, Lactiplantibacillus plantarum LP01 and Bifidobacterium longum 04 (n = 19) or placebo (n = 20). Fasting glucose, insulin, HOMA-IR, glucose-dependent insulinotropic peptide (GIP), high-sensitivity C-reactive protein (hs-CRP), lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14) and SCFAs were evaluated at three time points: baseline, week 6 and week 12. Between-group and treatment × time effects were analysed using general linear models. Results: Probiotic supplementation significantly reduced fasting glucose at 12 weeks compared with placebo (−1.8 vs. 0.1 mmol/L; p = 0.036). In the probiotic group, greater reductions in GIP (p = 0.012; p = 0.037), LBP (p < 0.001), sCD14 (p = 0.002; p = 0.001) and hs-CRP (p = 0.047) were also observed compared with placebo. Plasma SCFA concentrations remained largely unchanged, with no significant treatment × time interactions, except for higher valerate levels at 12 weeks in the probiotic group (p = 0.019). Conclusions: Twelve weeks of multi-species probiotic supplementation improved fasting glucose, reduced incretin and inflammatory biomarkers and attenuated metabolic endotoxemia, without alterations in circulating SCFAs. These findings support beneficial modulation of metabolic–immune pathways and highlight the promising role of probiotics to enhance glucose regulation and systemic inflammatory tone in adults with subthreshold depression. Full article

Oxidative stress is a critical pathophysiological factor in sepsis. Ursodeoxycholic acid (UDCA), a bile acid with anti-inflammatory, antioxidant, and anti-apoptotic properties, may protect against lipopolysaccharide (LPS)-induced myocardial injury. In an experimental study, 32 male Wistar rats were randomly assigned to four groups: control, LPS, UDCA, and UDCA + LPS. UDCA was administered orally for 10 days prior to LPS-induced endotoxemia. Serum levels of high-sensitive troponin I (hsTnI), homocysteine, and oxidative stress markers were measured, and immunohistochemistry and immunofluorescence were used to assess inflammation (nuclear factor kappa B, NF-κB), apoptosis (caspase 3), and signaling pathways related to protein kinase B (Akt)/NF-κB and silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1). UDCA pretreatment significantly reduced myocardial pathological changes, serum hsTnI, homocysteine, and total oxidative stress compared with LPS alone. It enhanced catalase (CAT) activity and glutathione (GSH) levels while lowering thiobarbituric acid reactive substances (TBARS) and nitrite concentrations in cardiac tissue. UDCA modulated cellular signaling by decreasing Akt phosphorylation and activating the SIRT1/Nrf2/HO-1 pathway. These results indicate that UDCA protects the heart from LPS-induced damage by reducing oxidative stress, inflammation, and apoptosis. UDCA modulates cellular signaling by decreasing pro-inflammatory pathways and activating anti-inflammatory pathways associated with SIRT1/Nrf2/HO-1 signaling, emphasizing its key role in myocardial protection during sepsis. Full article

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder in which gut microbiota dysbiosis contributes to insulin resistance, metabolic inflammation, and impaired glucose homeostasis. Dietary fibers and prebiotics selectively modulate gut microbiota composition and function and may offer metabolic benefits in T2DM. This review examines the mechanistic links between dietary fibers, prebiotics, gut microbiota modulation, and metabolic outcomes in T2DM. Methods: Relevant experimental and clinical studies were reviewed to assess the effects of dietary fibers and prebiotics on microbial diversity, short-chain fatty acid production, intestinal barrier function, bile acid signaling, and glycemic control in T2DM. Results: Evidence indicates that T2DM is associated with reduced abundance of SCFA-producing bacteria, increased intestinal permeability, metabolic endotoxemia, and altered bile acid metabolism. Dietary fibers and prebiotics enhance SCFA production, support gut barrier integrity, and modulate inflammatory and metabolic pathways. Clinical evidence demonstrates modest improvements in glycemic and inflammatory parameters, though outcomes vary according to fiber type, dose, and baseline microbiota composition. Conclusions: Dietary fibers and prebiotics are promising, low-risk strategies for gut microbiota modulation in T2DM. Further standardized, long-term randomized studies integrating microbiome profiling and clinically meaningful endpoints are required to support precision nutrition approaches. Full article

Cardiac resynchronization therapy (CRT) is a cornerstone intervention for patients with heart failure (HF) and electrical dyssynchrony, improving quality of life, functional capacity, and survival. Beyond mechanical synchrony, mounting evidence suggests CRT exerts systemic and myocardial cardiometabolic benefits. CRT acutely enhances mechanical efficiency and shifts substrate utilization toward greater oxidation of fatty acids and ketones, effects that correlate with long-term reverse remodeling on cardiac magnetic resonance imaging. Earlier metabolomic profiling demonstrated that CRT normalizes circulating energy metabolites, improving Krebs cycle intermediates and substrate balance between glucose and lipids, while baseline metabolite patterns may differentiate responders from non-responders. These metabolic adaptations accompany favorable changes in diastolic performance, right ventricular function, and ventriculo-arterial coupling. In parallel, improved splanchnic perfusion and reduced congestion may ameliorate gut dysbiosis and endotoxemia, mitigating systemic inflammation. Collectively, these findings position CRT as a therapy capable of both mechanical and metabolic restoration in advanced HF. In this review, we discuss the emerging data on how CRT reconditions myocardial energy metabolism, influences ventricular–arterial interactions, and modulates peripheral and gut-derived metabolic pathways. Full article