Search Results (2,328)

Objective: This study aimed to evaluate maternal serum afamin levels in women with intrahepatic cholestasis of pregnancy (ICP), examine their relationship with fasting bile acid concentrations, and assess their association with perinatal outcomes. Methods: This prospective case-–control study included 80 singleton pregnancies followed at a tertiary perinatology center between October 2025 and March 2026. Forty women with ICP, defined by pruritus and fasting bile acids > 10 μmol/L, were compared with 40 healthy pregnant controls. Women with ICP were further stratified according to fasting bile acid levels as <40 and ≥40 μmol/L. Maternal serum afamin concentrations were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Maternal characteristics, liver biochemistry, fetal biometric and Doppler parameters as well as obstetric and neonatal outcomes were compared. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of afamin for ICP, and logistic regression analysis was used to assess its association with ICP. Results: Baseline maternal characteristics were comparable between groups. Maternal serum afamin levels were significantly higher in the ICP group than in controls (6.18 ± 4.24 vs. 3.98 ± 1.95 ng/mL, p = 0.004). Afamin correlated positively with fasting bile acids (r = 0.372, p = 0.018), but not with transaminases, gestational age at delivery, birth weight, or neonatal outcomes. In logistic regression, afamin was independently associated with ICP (adjusted odds ratio [aOR] 1.260; 95% confidence interval [CI] 1.059–1.500; p = 0.009). ROC analysis showed poor discrimination for ICP (area under the curve [AUC] 0.634, 95% CI 0.51–0.76, p = 0.039), whereas afamin did not discriminate between subgroups defined by fasting bile acid levels (<40 vs. ≥40 μmol/L). The optimal cut-off value of 4.93 ng/mL predicted ICP with 55% sensitivity, 67.5% specificity, a positive likelihood ratio of 1.69, and a negative likelihood ratio of 0.67. Conclusions: Maternal serum afamin levels are elevated in ICP and show a modest association with fasting bile acid burden. Its discriminatory performance is limited, and it does not reliably distinguish patients defined by a ≥40 μmol/L threshold. These findings suggest that afamin reflects the maternal response to cholestasis rather than disease severity and may serve as a complementary biomarker. Full article

The sodium-taurocholate cotransporting polypeptide (NTCP) plays a critical dual role in liver function: maintaining bile acid (BA) enterohepatic circulation and acting as a receptor for the entry of hepatitis B and D viruses into hepatocytes. This review outlines the impact of various post-translational modifications (PTMs) of NTCP—including phosphorylation, oligomerization, ubiquitination, and glycosylation—on its dynamic regulatory network. These modifications coordinate the modulation of NTCP’s membrane localization, stability, conformational state, and protein interactions, precisely controlling its functions in BA uptake and viral invasion. Targeting this PTM network presents a promising strategy for next-generation therapies that selectively inhibit viral infection while preserving BA transport, overcoming the limitations of conventional inhibitors that indiscriminately disrupt virus–NTCP interactions. By synthesizing recent insights into NTCP PTM research, this article highlights its role as a central regulator of its bifunctional properties and reveals potential avenues for precision therapies in viral hepatitis, cholestasis, and related liver diseases. However, most existing evidence is derived from in vitro or cell-based models, whereas in vivo studies and clinical validation remain limited; thus, the translational feasibility of strategies targeting post-translational modifications of NTCP still requires further investigation. Full article

Tuberculosis (TB) remains a major global cause of morbidity and mortality. Current tools for monitoring treatment response rely on sputum-based microscopy and culture, which are often insensitive, time-consuming, and impractical in extrapulmonary or pediatric TB and in individuals unable to produce sputum. Metabolomics has emerged as a promising approach for identifying host-derived biomarkers that reflect treatment-associated immunometabolic changes; however, the available evidence remains heterogeneous and has not been comprehensively synthesized. We conducted a comprehensive literature review of human studies evaluating metabolomic biomarkers in relation to TB treatment response or outcomes. PubMed, Scopus, and EMBASE were searched for human studies evaluating targeted or untargeted metabolomics (NMR, LC-MS, GC-MS, CE-MS) in relation to treatment response or outcomes. Two reviewers independently screened studies, extracted data, and assessed risk of bias using QUIPS and PROBAST. Findings were synthesized using a structured framework organized across treatment stages and outcomes. Of 218 records identified, 139 titles and abstracts were screened and 42 full texts assessed; 15 studies met the inclusion criteria. Recurrent treatment-associated signals involved amino acid metabolism, particularly the tryptophan–kynurenine pathway, as well as vitamin and cofactor metabolites (pyridoxate, nicotinamide, trigonelline). Plasma studies frequently reported lipid remodeling and bile acid perturbations, whereas urine studies highlighted polyamine metabolism (e.g., N¹,N¹²-diacetylspermine) and fatty acid β-oxidation markers. Common limitations included inadequate adjustment for confounders and, in prediction models, small sample sizes and limited external validation. Metabolomics reveals reproducible but heterogeneous immunometabolic changes during TB therapy. Key pathways include tryptophan–kynurenine metabolism, vitamin and cofactor metabolism, lipid remodeling, and urine polyamine pathways. Standardization and prospective multicenter validation are needed for clinical translation. Full article

The significance of less abundant genera within the gut microbiota, such as Parabacteroides, remains largely unexplored. Despite its low levels, Parabacteroides is highly conserved and potentially beneficial across populations. This trial aimed to evaluate whether a four-week intake of glucolacto-oligosaccharides (GLO), previously reported as an enhancer of Parabacteroides, improves defecation frequency as the primary outcome. It also assessed holistic gut health and underlying microbiota-based mechanisms. In this randomized, double-blind, placebo-controlled trial, 50 healthy Japanese participants with a defecation frequency of five or fewer times per week were enrolled. The mean (±SE) weekly defecation frequency in the GLO group was 3.2 ± 0.2 at baseline, increasing to 5.8 ± 0.6 at week 4, whereas that in the placebo group was 3.4 ± 0.3 at baseline, increasing to 4.4 ± 0.3 at week 4. The time-dependent weekly defecation frequency was significantly higher in the GLO group than in the placebo group (p = 0.029). Changes in the relative abundance of the genus Parabacteroides significantly increased in the GLO group compared with in the placebo group. Changes in fecal bile acid composition were also confirmed in the GLO group compared with the placebo group, which was thought to be due to the unique features of Parabacteroides. Furthermore, changes in alpha diversity indices were significantly higher in the GLO group than in the placebo group (Simpson, p = 0.041; Pielou, p = 0.022). Additional analysis demonstrated that the increase in alpha diversity in the GLO group was significantly correlated with the increase in the relative abundance of Parabacteroides (p = 0.006), which tended to be associated with decreases in serum gamma-glutamyltransferase (p = 0.089) and serum triglyceride (p = 0.075) levels. These data suggest that GLO intake improved defecation status, selectively increased Parabacteroides, and harmonized the gut environment. Full article

Microbiome-based therapies are reshaping the therapeutic landscape for ulcerative colitis (UC), offering new avenues for disease management beyond conventional immunomodulatory and biologic treatments. UC remains a chronic, relapsing condition with significant unmet clinical needs, as many patients fail to achieve sustained remission or experience adverse effects with current therapies. The gut microbiome has emerged as a central contributor to UC pathogenesis, influencing epithelial barrier integrity, immune homeostasis, and metabolic signaling. Interventions such as fecal microbiota transplantation (FMT) and defined microbial consortia have demonstrated proof-of-concept efficacy in early-phase clinical trials, each leveraging distinct mechanistic strategies. FMT, as a broad ecological intervention, restores microbial diversity and functional redundancy, potentially addressing multiple pathogenic mechanisms simultaneously. In contrast, defined consortia enable precise targeting of specific metabolic and immunological pathways, including short-chain fatty acid production, bile-acid remodeling, epithelial barrier reinforcement, immune modulation, and succinate degradation. Recent clinical evidence suggests that consortia with broader mechanistic coverage may achieve more consistent biological activity than narrowly focused designs. This review synthesizes mechanistic and clinical insights across broad and defined microbial consortia, integrates evidence from randomized controlled trials and early-phase LBP studies, and outlines a precision-medicine framework to guide therapy selection. We highlight the importance of aligning therapeutic mechanisms with patient-specific microbial, metabolic, and immune profiles, and discuss future directions including biomarker-guided stratification, hybrid consortia, and adaptive trial designs. Advancing both broad and defined approaches, while incorporating ecological principles, mechanistic understanding, and patient stratification, will be essential to realizing the full therapeutic potential of microbiome-based therapies in UC. Full article

Background: Oxidative liver damage, fibrosis, cirrhosis and liver failure are caused by reactive oxygen species and inflammatory responses triggered by bile retention during prolonged cholestasis. Pomegranate and persimmon fruits, which are loaded with bioactive compounds that have anti-inflammatory and antioxidant properties, were evaluated separately for their efficacy in preventing oxidative stress and inflammation in cholestasis. Methods: Pomegranate and persimmon juices were analyzed for their vitamin C, carotenoids and organic acid levels, phenolic profile, and antioxidant activity. Liver protection against oxidative stress and inflammation brought on by cyclosporine-induced cholestasis in rats was verified by biochemical measurements, metabolite identification, and histopathologic examination. To forecast the mechanism of pomegranate and persimmon anti-inflammatory action, an in silico assessment was also carried out. Results: Vitamin C levels in pomegranate and persimmon juices were 99.55 and 51.75 µg/g, respectively. In both pomegranate and persimmon juices, gallic acid was the most prevalent phenolic compound (123.20 and 50.69 µg/g, respectively). Pomegranate and persimmon juices significantly (p < 0.05) reduced the rise in liver values of MDA, NO, TNF-α, IL-6, IL-1β, and TLR4, as well as serum values of total and direct bilirubin caused by cyclosporine. Additionally, the alteration of metabolites, particularly amino acids, demonstrated the inhibitory effect of pomegranate and persimmon juices on liver damage. Gallic acid’s and catechin’s substantial binding affinities with target inflammatory cytokines (TNF-α and TLR4) were further validated by molecular docking. Conclusions: These results showed that pomegranate and persimmon juices mainly modulated inflammation and oxidative stress to provide hepato-protective benefits against cyclosporine-induced cholestatic liver injury. Full article

Background: This study investigated the mechanisms underlying diarrhea induced by a high-fat diet (HFD) under a state of fatigue, focusing on gut microbiota dysbiosis, bile acid metabolic disturbance, and gut–liver injury. Methods: Mice were assigned to a normal control diet (NCD) group, a HFD-induced diarrhea under fatigue (HFDM) group, and a HFD-induced diarrhea with aggravated dysbiosis (HFDMA) group. Histopathology, inflammatory factors, intestinal barrier-related proteins, small-intestinal microbiota, and colonic bile acid profiles were assessed, and correlation analyses were performed among gut microbiota, bile acids, and inflammatory factors. Results: Compared with the NCD group, both the HFDM and HFDMA groups showed diarrhea-like and fatigue-like phenotypes, histopathological injury in the small intestine and liver, increased tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels, and impaired intestinal barrier function. No significant differences in inflammatory factors were observed between the HFDM and HFDMA groups. Zonula occludens-1 (ZO-1) expression decreased in both model groups but reached statistical significance only in the HFDMA group, whereas Claudin-1 expression was significantly reduced in both groups. Gut microbiota analysis showed altered community structure, with downward trends in alpha diversity that did not reach statistical significance but clear separation trends in beta diversity. Proteobacteria and Streptococcus increased, whereas Ligilactobacillus decreased. Total bile acid levels did not differ significantly among groups; however, the ratio of secondary to primary bile acids was significantly reduced in both model groups, particularly in the HFDMA group, with decreases in representative secondary bile acids, including hyodeoxycholic acid (HDCA) and isolithocholic acid (isoLCA). Correlation analysis further supported close associations among gut microbial alteration, bile acid disturbance, and intestinal and hepatic inflammation. Conclusions: Gut microbiota dysbiosis may disrupt bile acid metabolism, impair intestinal barrier integrity, and promote intestinal and hepatic inflammatory responses, thereby contributing to diarrhea progression under fatigue and HFD conditions through the gut–liver axis. Full article

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are consistently associated with alterations in gut microbial communities, although the extent and characteristics of these alterations vary across studies, supporting a potential role of the microbiota in disease pathogenesis and therapeutic modulation. We conducted a systematic review to synthesize current evidence on microbiota alterations in IBD and the clinical application of fecal microbiota transplantation (FMT). A total of 118 studies were included (76 focused on microbiota profiling and 42 evaluated FMT as therapy). Across heterogeneous study designs and microbial characterization methods, reduced microbial diversity was the most consistently reported alteration, generally more pronounced in CD than in UC. Depletion of Faecalibacterium prausnitzii—a key butyrate producer with anti-inflammatory properties—was commonly reported, often accompanied by functional impairment in short-chain fatty acid production. Microbial patterns were frequently associated with mucosal inflammation and varied across disease phenotypes; these patterns have been increasingly explored as predictors of treatment response and relapse, although mechanistic interpretation remains limited and causal relationships are difficult to establish. Evidence from randomized controlled trials suggests potential efficacy of FMT in UC, particularly with intensive or repeated protocols, whereas data in CD remain limited and heterogeneous, with signals of benefit often appearing transient. FMT was generally well tolerated, but long-term safety data remain scarce. Emerging multi-omic approaches are reshaping the field by integrating taxonomic and functional insights, with potential implications for risk stratification, diagnosis, prognosis, and therapeutic optimization. Further standardized, longitudinal, and mechanistically oriented studies are required to translate microbiome research into clinically actionable strategies in IBD. Full article

Background/Objectives: The growing prevalence of obesity necessitates innovative gut-targeted material strategies to modulate diet-associated metabolic dysfunction. This study investigates a spray-dried konjac glucomannan–montmorillonite (KGM-MMT) hybrid designed to integrate fermentable polysaccharide properties with luminal lipid-adsorptive clay functions within a single micro-engineered formulation. Methods: In HFD-fed mice treated for 42 days with 2% w/w KGM-MMT, cumulative body weight gain was attenuated by 7.6%, with an AUC of 5094 ± 52.95, compared to 5513 ± 81.35 in HFD controls (p < 0.0001). Results: Serum IL-6 concentrations were reduced by 97% (p = 0.0002), while blood glucose decreased by 46% (p < 0.0001); these effects were greater than those observed with MMT (24%, p = 0.0271) and KGM (16%, ns). Gut microbiota profiling demonstrated a significant 6.2-log₂-fold increase in Lactobacillaceae (p = 0.023) and a 2.4-log₂-fold increase in Enterococcaceae (p = 0.015) following KGM-MMT treatment. Functional shifts inferred from 16S rRNA gene-based prediction indicated a 1.9-fold increase in short-chain fatty acid-related pathways and a 5.4-fold increase in bile acid deconjugation pathways. Conclusions: Although the KGM-MMT hybrid did not consistently outperform its individual components across all endpoints, it consolidated complementary KGM- and MMT-associated effects within a single dosage form. These findings support spray-dried KGM-MMT as a gut-targeted biomaterial strategy that integrates multiple luminal and microbiota-associated functions within a single formulation. Future studies should define dose–response relationships, validate microbiota-derived functional predictions using higher-resolution approaches, and assess durability and safety under longer-term exposure. Full article

Obesity, a heterogeneous metabolic disease, is linked with severe comorbidities, prominently increasing morbidity and mortality. A weight loss between 5% and 10% is already sufficient to induce clinically relevant improvements in human health. Activation of energy expenditure through an impact on the brown and beige adipose tissues has recently become an interesting new target in obesity treatment. Obeticholic acid (OCA) is a semisynthetic derivative of the primary human bile acid, chenodeoxycholic acid. The compound is an agonist of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor (TGR5), activating the cellular pathways such as fibroblast growth factor-19, tissue-specific uncoupling protein 1, or type 2 iodothyronine deiodinase associated with energy expenditure and brown adipose tissue activity. So far, OCA has been approved to treat primary biliary cholangitis. Interestingly, the drug demonstrated therapeutic effects in animal models of obesity. Preliminary results from the human studies show that OCA administration holds potential as a treatment option in obesity, although some adverse effects may occur. Long-term administration of OCA might constitute an attractive therapeutic add-on approach, complementary to the currently approved treatments. The design of OCA derivatives targeting similar mechanisms, yet with a better pharmacological profile, seems to be an exciting pathway in the search of novel anti-obesity drugs. Further clinical trials involving larger cohorts of patients, with and without comorbidities, are warranted to confirm the benefits and safety of OCA administration. Full article

Background: Acute rejection remains a major complication following liver transplantation, yet reliable noninvasive biomarkers for its early prediction and diagnosis remain unidentified. This exploratory study characterized bile and serum metabolites associated with acute rejection in living donor liver transplantation using comprehensive metabolomic profiling combined with machine learning. Methods: Non-targeted metabolomics were performed on bile samples collected on post-operative day (POD) 1 (n = 38) and serum on POD 14 (n = 45) from liver transplant recipients. Partial least squares discriminant analysis-based variable selection was followed by logistic regression and least absolute shrinkage and selection operator models, which were evaluated via cross-validation in the discovery cohort to explore potential biomarkers for acute rejection. Results: A three-variable, bile-based model for predicting acute rejection achieved a mean cross-validated AUC of 0.872 (95% confidence interval: 0.814–0.930). Glycohyocholic acid and sulfolithocholylglycine were the main contributors. A nine-variable serum model for the Rejection Activity Index, including the change in γ-glutamyl transferase, showed a mean cross-validated R² of 0.728 (95% confidence interval: 0.609–0.846), with methionine, creatine, and oxidized fatty acids contributing prominently. Conclusions: These findings suggest that metabolomic profiling combined with machine learning may provide candidate biomarkers for acute rejection after liver transplantation. However, given the exploratory nature of the study and the lack of external validation, the clinical utility of these metabolite signatures remains to be determined. Therefore, external validation in larger, independent cohorts will be required. Full article

Microbiome research is shifting from a focus on “whole microorganisms” to an emphasis on microbial functional components. This review systematically describes how the effects of microbial communities on the host are mediated by bioactive functional components released by microbes. These components primarily exert their effects through interactions with host Pattern Recognition Receptors (PRRs) and metabolic sensing receptors, thereby regulating host immune, metabolic, and barrier function networks. The biological effects of these functional components are highly context-dependent. Under homeostasis, metabolites such as SCFAs and bile acids promote mucosal immune tolerance and maintain epithelial barrier integrity. However, the same signals can become deleterious under dysbiosis, driving inflammation and contributing to colorectal tumorigenesis. Mechanistic dissection of individual components, such as lipopolysaccharide (LPS), is now propelling a transition in clinical translation from whole-microbe-based interventions toward component-oriented diagnostics and therapeutics. Component-oriented diagnostics and therapeutics use defined microbial molecules rather than whole microorganisms. Microbial nucleic acids (e.g., HPV DNA), metabolites (e.g., SCFAs), and proteins can serve as biomarkers for disease risk, diagnosis, and prognosis. Therapeutic strategies include targeted modulation of beneficial components, neutralization of harmful molecules, and engineered microbial delivery. Full article

Background: Lactopontin (L-OPN) is a pivotal bioactive protein present in breast milk that supports bone development, but its efficacy in a formula matrix is unknown. This study aimed to evaluate the effects of L-OPN-fortified formula on bone growth in a growing rat model and to explore the underlying mechanisms. Methods: Weanling rats (n = 8/group) received daily gavage for four weeks: (1) CON—deionized water; (2) PRO—750 mg/kg·BW mixed protein; or (3) L-OPN—750 mg/kg·BW of the PRO formula fortified with L-OPN. Results: The results showed that the formula fortified with L-OPN could significantly increase bone volume and trabecular bone number (p < 0.05). Furthermore, both femur length and thickness, as well as overall body length, were significantly increased (p < 0.001). In addition, the L-OPN-fortified formula specifically increased the relative abundance of Bacteroides and Parabacteroides in rat feces (p < 0.05). Metabolomic analysis revealed that L-OPN supplementation significantly altered bile acid metabolism, notably increasing serum levels of 12-ketolithocholic acid (12-KLCA), which correlated strongly with bone metrics. Conclusions: These preclinical findings provide a basis for future research in infant formula. Full article

Interactions between alcohol and nutrition play an important role in the development and progression of alcohol-associated liver disease (ALD). Although dietary cholesterol was shown to exacerbate fatty liver and liver injury in alcohol-fed mice, findings regarding the combined effect of dietary cholesterol and heavy alcohol drinking on cholesterol homeostasis remain controversial. Ezetimibe has been widely used as a cholesterol-lowering drug in hypercholesterolemic subjects. It is not fully understood whether ezetimibe blunts the adverse effect of cholesterol on lipid and biliary bile acid metabolism in alcohol-exposed mice. In the current study, wild-type mice were subjected to NIAAA alcohol feeding model. Dietary cholesterol (0.2%, w/v) and ezetimibe (0.001%, w/v) were added to the liquid diets. Cholesterol and triglyceride contents in the liver and circulation were determined. Biliary bile acid composition, as well as hepatic and circulating inflammatory markers were analyzed. We found that ezetimibe protected mice from the synergistic effects of dietary cholesterol and alcohol on hepatic triglyceride accumulation, which was accompanied by enhanced expression of genes involved in hepatic beta oxidation. Dietary cholesterol caused great increases in liver cholesterol content and dramatic reductions in the expression of hepatic cholesterol biosynthetic genes in both control- and alcohol-fed mice. These changes were normalized by ezetimibe treatment. Ezetimibe attenuated dietary cholesterol-induced elevations in total biliary bile acids. Moreover, mice fed a diet containing both cholesterol and alcohol exhibited increased expression of monocyte chemoattractant protein 1 (Mcp1) and tumor necrosis factor alpha (Tnfα) in the distal small intestine. Collectively, our findings indicate that ezetimibe effectively mitigates the adverse effects of dietary cholesterol and alcohol consumption on hepatic lipid accumulation and liver injury. 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