Search Results (625)

Chronic liver diseases impose a considerable global public health burden, yet available treatment options remain largely inadequate. The gut microbiota exerts a key modulatory effect on liver disease pathogenesis via the gut-liver axis. Among them, Lachnospiraceae, a dominant bacterial family in the healthy adult gut, has drawn growing interest in recent years. Lachnospiraceae exert protective functions by producing short-chain fatty acids, participating in secondary bile acid conversion, and synthesizing active metabolites such as N-acetyl-glutamic acid, thereby maintaining intestinal barrier integrity and regulating host metabolic and immune homeostasis. Extensive evidence indicates that in cirrhosis, alcohol-associated liver disease, and metabolic dysfunction-associated steatotic liver disease, Lachnospiraceae abundance is consistently and significantly reduced, and this decrease is closely correlated with disease severity and adverse prognosis. In hepatocellular carcinoma, however, different members of Lachnospiraceae exhibit functional divergence, with some butyrate-producing genera decreasing while other subgroups may become enriched and influence the tumor immune microenvironment. Live biotherapeutic products based on Lachnospiraceae have achieved clinical breakthroughs in recurrent Clostridioides difficile infection and metabolic syndrome, providing important references for their translational application in liver diseases. This review systematically synthesizes the abundance changes and mechanisms of Lachnospiraceae across major liver diseases, evaluates their biomarker and therapeutic target potential, and seeks to provide fresh perspectives for precision microbiome-modulating strategies in chronic liver disease management. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to Western dietary patterns. Yet, preclinical studies rely on continuous high-fat feeding, overlooking the intermittent nature of human eating. Whether dietary periodicity itself influences the gut–liver axis and MASLD pathogenesis remains unknown. We compared continuous and intermittent high-fat, high-cholesterol (HFHC) diets in guinea pigs, a model that mirrors human lipoprotein metabolism, hepatic cholesterol handling, and hindgut fermentation. Methods: Integrated multi-omics analyses (serum metabolomics, fecal 16S rRNA sequencing, and liver transcriptomics) were employed in a guinea pig model, stratified into normal diet (ND), intermittent HFHC diet (IHD), and IHD with flaxseed lignan supplementation, to compare the effects of dietary regimens and the therapeutic efficacy of lignan on hepatic pathology. Results: Both diets induced hallmark hepatic features of MASLD; however, the intermittent regimen provoked significantly more severe hepatic steatosis, inflammation, oxidative stress, and fibrosis. Hepatic transcriptomic analysis identified the PI3K-Akt signaling pathway as the most significantly enriched pathway in the IHD group. Mechanistically, this aggravated liver injury was linked to gut microbiota dysbiosis and a marked depletion of the microbial metabolite enterolactone. Fecal microbiota transplantation confirmed that the dysbiotic microbiota directly transmits the aggravated liver injury phenotype. Supplementation with flaxseed lignan, the dietary precursor of enterolactone, restored enterolactone production, corrected the dysregulated gut microbiota–enterolactone axis, and largely normalized the expression of PI3K-Akt downstream targets, thereby alleviating hepatic pathology. Conclusions: These findings suggest that alterations in the gut microbiota–enterolactone axis may contribute to diet-periodicity-driven liver injury and highlight its potential involvement in disease progression. Modulating this axis through dietary interventions, such as flaxseed lignan supplementation, may represent a promising nutritional strategy for mitigating MASLD associated with cyclical dietary exposure. Full article

Aflatoxin B₁ (AFB₁) is a prevalent mycotoxin contaminating food and environmental matrices that can induce hepatic injury, thereby posing a substantial threat to livestock production. Portulaca oleracea L. polysaccharide (POP) possesses diverse biological activities, including antioxidant and anti-inflammatory properties. However, the protective effects of POP against AFB₁-induced hepatic injury have not been fully elucidated. In the present study, a rabbit model of AFB₁-induced hepatic injury was established to investigate the hepatoprotective mechanisms of POP. Histopathological examination and liver function assessments demonstrated that POP markedly ameliorated hepatic histopathological alterations and decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Molecular analyses further demonstrated that POP attenuated AFB₁-induced oxidative stress and hepatocyte apoptosis, effects that were associated with activation of the PI3K/AKT signaling pathway and suppression of the mitochondria-mediated apoptotic pathway. Furthermore, microbiome profiling and targeted short-chain fatty acid (SCFA) metabolomics analyses indicated that POP supplementation contributed to the preservation of intestinal barrier integrity and intestinal microbiota stability, concurrent with the attenuation of AFB₁-induced intestinal and hepatic injury and elevated SCFA production by intestinal microbes. Overall, POP exerts prominent preventive protective effects against AFB₁-induced liver injury, which may be closely associated with alterations in intestinal microbiota composition and microbial short-chain fatty acid metabolism, as well as the activation of the PI3K/AKT signaling pathway. These findings provide novel insights into the mechanisms underlying AFB₁-induced hepatic injury. Full article

Primary sclerosing cholangitis (PSC) is a rare cholangiopathy strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis. PSC-IBD defines a clinically quiescent but biologically aggressive colitis phenotype, characterized by extensive yet often asymptomatic mucosal inflammation and disproportionately elevated risks of colorectal cancer—approximately 3- to 5-fold higher than in IBD alone—and cholangiocarcinoma (CCA), with IBD comorbidity representing an independent risk factor for hepatopancreatobiliary malignancy. The pathogenesis remains incompletely understood but involves genetic susceptibility, immune dysregulation—including aberrant lymphocyte trafficking and an imbalance between T helper 17 (Th17) and regulatory T (Treg) cells—intestinal barrier dysfunction, and gut–liver axis perturbations involving alterations in the microbiota and bile acid homeostasis. Within the biliary tree, chronic inflammation activates peribiliary glands (PBGs), which harbor stem/progenitor cells. PBG hyperplasia may contribute to periductal fibrosis through Hedgehog signaling and epithelial-to-mesenchymal transition and may represent a key step in PSC-associated cholangiocarcinogenesis. The true burden of PSC-IBD is likely underestimated, as PSC may remain clinically silent for years. Bidirectional screening is therefore essential: all patients with PSC should undergo ileocolonoscopy with biopsies regardless of symptoms, whereas patients with IBD and cholestatic liver biochemistry—particularly elevated gamma-glutamyl transferase or alkaline phosphatase—should undergo magnetic resonance cholangiopancreatography. No medical therapy has demonstrated a clear ability to alter the natural history of PSC, and liver transplantation remains the only definitive treatment for advanced disease. This review integrates current evidence on the epidemiology, pathophysiology, and management of PSC-IBD, critically examining unmet needs in timely diagnosis, mechanistic understanding, and therapeutic development, with particular attention to non-invasive biomarkers, microbiota-directed strategies, individualized risk stratification, and disease-modifying endpoints. Full article

Broodiness is a natural behavior whereby female birds stop laying eggs to sit on and hatch them. This behavior is regulated through genetic, hormonal, and environmental factors. The Taihe Black-Boned Silky Fowl (TBSF), a Chinese traditional domestic breed, exhibits a strong brooding tendency; however, the molecular mechanisms underlying this trait remain unclear. In this study, we performed an integrated multi-omics analysis to characterize differences between two groups of TBSF hens: 8 individuals undergoing 30 days of active brooding (BR30) and 8 individuals in the normal laying egg stage (NB), selected from a total group of 230 hens. We combined 16S rRNA sequencing, untargeted metabolomics, and hepatic transcriptome sequencing, with statistical analyses including QIIME 1.9.1, OPLS-DA (VIP > 1), Student’s t-test (p ≤ 0.05), and DESeq2 (|log₂FC| ≥ 1, FDR < 0.05) for differentially expressed genes (DEGs), respectively, and Pearson’s correlation analysis for multi-omics integration. Phenotypically, brooder hens showed significantly reduced feed intake, body weight, and main digestive tissue indices, alongside altered liver and blood biochemical parameters. Hepatic transcriptome analysis identified 1582 DEGs between groups, enriched in pathways related to fatty acid oxidation and the amino acid degradation pathway. In addition, 16S rRNA sequencing revealed distinct gut microbial community structures: the NB group was enriched in Bacilliota and Pseudomonadota, while the BR30 group was enriched in Spirochaetota and Synergistota. Metabolomic profiling identified a total of 143 differential metabolites, which were enriched in lipid and amino acid metabolites, including alpha-linolenic acid and pyruvate metabolites. Multi-omics correlation analysis revealed tight associations between gut microbial taxa, circulating metabolites, and hepatic gene expression. Specifically, beneficial lipid metabolites, including phospholipids, lysophosphatidylcholines, and sphingomyelins, were positively correlated with Synergistes and the Christensenellaceae R-7, as well as with key hepatic lipid metabolism genes FABP1, LPL, and FADS2. In summary, this study reveals that the gut–liver axis plays a critical part in the modulation of energy metabolism during broodiness, and further highlights new insights into metabolic targets that could optimize reproductive behavior and enhance poultry production. Full article

Background/Objectives: Alcohol-associated liver disease (ALD) is driven by gut-liver axis dysfunction, including intestinal barrier disruption, dysbiosis, microbial translocation, inflammation, metabolic dysfunction, and malnutrition. Fermented dairy foods may modulate several of these domains, yet whether sheep yogurt, as an intact fermented dairy matrix, is relevant in ALD is unknown. This scoping review mapped evidence relevant to sheep yogurt, ALD, and gut-liver axis biology. Methods: A PRISMA-ScR-guided scoping review searched PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar from January 2006 to February 2026. Eligible sources were charted using a prespecified framework classifying evidence as direct, indirect, or mechanistic inference. Mapped domains included ALD pathophysiology; intestinal barrier integrity; bacterial and fungal microbial ecology; bile acid and tryptophan-aryl hydrocarbon receptor signaling; nutritional vulnerability; fermented dairy interventions; and ovine dairy-matrix characteristics. Results: Of 1388 records identified, 121 sources were included after duplication and screening. No eligible study directly tested sheep yogurt or a defined sheep yogurt preparation in ALD-relevant experimental or clinical settings. Indirect evidence supported the relevance of gut-liver axis dysfunction to ALD and indicated that selected fermented dairy products, probiotics, postbiotics, and microbial preparations may influence intestinal permeability, inflammatory signaling, microbial ecology, oxidative stress, and liver-injury outcomes. Compositional data supported sheep yogurt as a distinct food matrix. However, findings from isolated components, probiotic-only interventions, and non-ALD models could not be interpreted as evidence of sheep yogurt efficacy in ALD. Conclusions: The current literature supports a hypothesis-driven research framework rather than any therapeutic claim for sheep yogurt in ALD. Any potential benefit of sheep yogurt in ALD remains hypothetical and cannot support clinical or dietary recommendations until validated experimentally. Future direct, comparator-controlled studies of intact sheep yogurt should assess liver injury, barrier integrity, microbial translocation, relevant metabolites, and nutrition-related outcomes. Full article

Short stature is a common pediatric endocrine–metabolic disorder characterized by impaired linear growth and increased risks of adverse health outcomes. Although previous reviews have summarized associations between gut microbiota and childhood health, few have focused on the mechanistic links among microbial composition, microbial-derived metabolites, endocrine regulation, and skeletal growth in short stature. This review provides an integrated framework exploring the potential interactions among gut microbiota composition, microbial-derived metabolites, endocrine regulation, and skeletal development in short stature. We summarize the clinical characteristics and epidemiological features of major short stature subtypes and discuss emerging evidence demonstrating the involvement of gut microbiota alterations and metabolite dysregulation in growth regulation. Particular attention is given to the bidirectional interactions between the gut microbiota and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, as well as the potential role of the gut–liver–bone axis in skeletal growth. Furthermore, this review integrates evidence from metabolomics studies, experimental animal models, and microbiota-targeted interventions to provide mechanistic insights into microbiota-mediated growth regulation. Dietary factors, physical activity, sleep, antibiotic exposure, probiotic interventions, and current clinical treatments are also discussed from the perspective of microbiota modulation. Despite increasing interest in microbiota-based strategies, clinical translation remains limited by insufficient functional validation, unclear causal relationships, and a lack of well-designed intervention trials. Future integration of functional microbiology, multi-omics approaches, and human-based validation platforms may facilitate the development of microbiome-based precision interventions for improving growth outcomes in children with short stature, particularly those with ISS. Full article

Background/Objectives: Metabolically dysregulated-associated steatotic liver disease (MASLD) is a complex, multifactorial disorder characterised by hepatic lipid accumulation, insulin resistance, oxidative stress, and dysfunction of the gut–liver axis. Given its intricate pathophysiology, multi-target nutritional strategies represent a promising complementary approach. This study aimed to evaluate the biological effects of a multi-component nutraceutical formulation using an integrated in vitro platform replicating intestinal, hepatic, and pancreatic–liver interactions. Methods: The formulation was tested on Caco-2 intestinal cells to assess cell viability, transepithelial electrical resistance (TEER), probiotic functional properties, and glucose absorption. Intestinally processed metabolites were then applied to HepaRG liver cells under hyperglycemic (glucose) or lipotoxic conditions (oleic acid/palmitic acid) to analyse lipid accumulation, cholesterol biomarkers (HMGR, LDL), bile acid production, and cellular damage (ALT, AST). Finally, a pancreas–liver co-culture model (EndoC-βH5 and HepaRG) was employed to investigate insulin secretion and downstream hepatic metabolic signalling (IRS1, GLUT2, glycogen). Results: The formulation preserved intestinal barrier integrity and enhanced probiotic functionality, including aggregation and hydrophobicity. In hepatic models, the treatment significantly reduced intracellular lipid accumulation and triglycerides, while increasing bile acid production and improving cholesterol profiles. Under steatotic stress, it lowered transaminase levels and downregulated lipogenic signalling. In the pancreas–liver axis model, the formulation restored glucose-stimulated insulin secretion and improved hepatic metabolic signalling by increasing IRS1 levels and glycogen synthesis, indicating enhanced insulin sensitivity. Conclusions: These findings support the biological plausibility of a multi-target nutraceutical approach for MASLD. The formulation demonstrates coordinated beneficial effects on intestinal barrier function, hepatic lipid management, and glucose metabolism, providing a strong rationale for further clinical investigation. Full article

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

Overwintering represents a critical bottleneck for farmed fish, during which low temperature and starvation stress frequently co-occur, yet their synergistic effects on fish health remain poorly understood. Here, we exposed Pelteobagrus vachelli, a cold-sensitive freshwater species, to four conditions for 10 days: control (25 °C, feeding), starvation alone (25 °C, starvation), cold alone (11 °C, feeding), and combined cold–starvation (11 °C, starvation). Hepatic histopathology, antioxidant and liver function indices, gut microbiota (16S rRNA sequencing), and untargeted metabolomics (LC–MS) were integrated to elucidate gut–liver axis mechanisms underlying synergistic injury. Combined stress synergistically aggravated liver injury, as evidenced by hepatocellular vacuolation and necrosis, elevated aspartate aminotransferase (AST), alanine transaminase (ALT), malondialdehyde (MDA), and suppressed total superoxide dismutase (T–SOD), glutathione (GSH), catalase (CAT), and total antioxidant capacity (T–AOC). Two-way ANOVA confirmed significant interactive effects between cold and starvation stress (p < 0.05). Multi-omics revealed that dual stress uniquely activated multiple cell death pathways (FoxO, autophagy, ferroptosis, apoptosis), with marked oxidative phosphorylation (OXPHOS) activation and glutathione depletion—a signature absent under single stressors. Gut microbiota restructuring showed beneficial commensals (Cetobacterium, Prevotella, Lactobacillus) depleted and opportunistic pathogens (Plesiomonas, Pseudomonas, Flavobacterium) enriched, with Plesiomonas identified as the dominant biomarker (LDA score = 5.32). Integrative networks identified these pathogenic genera as hubs linking metabolic dysregulation to liver damage. Collectively, combined cold–starvation induces synergistic liver injury via gut–liver axis disruption, driving metabolic reprogramming and oxidative damage. These findings provide candidate biomarkers for overwintering stress monitoring and inform management strategies to mitigate cold–starvation-induced hepatic injury in aquaculture. Full article

Background: Inflammatory bowel disease is a complex intestinal inflammatory disorder linked to immune dysregulation, oxidative stress, and an imbalance in the gut microbiota. Grape seed flour (GSF), a winemaking by-product rich in polyphenols and fibres, displays antioxidant and anti-inflammatory properties and may help maintain gut homeostasis. Methods: The phenolic composition and antioxidant capacity of our GSF were evaluated. We assessed whether a diet containing 10% (w/w) GSF protects against dextran sulphate sodium (DSS)-induced acute colitis in BALB/c mice. Animals received either a standard diet or a GSF-supplemented diet before and during DSS exposure. Body weight and disease activity index were monitored. At sacrifice, colon length and colonic histology scoring were measured. The study of the faecal microbiota and predicted genome was performed using PICRUSt. Caecal metabolites, including short-chain fatty acids, were also quantified. Results: GSF is rich in fibres (64%) and exhibits a very high polyphenolic content and high antioxidant capacity. GSF supplementation attenuated DSS-induced weight loss and disease activity and limited colonic shortening and histological damage. It also improved biomarkers of colon, mesenteric lymph nodes (MLNs), and liver injury. At the molecular level, GSF downregulated key pro-inflammatory mediators in the colon and liver, while enhancing anti-inflammatory (e.g., IL-10) and antioxidant markers, indicating reinforcement of regulatory and redox-protective pathways along the gut–liver axis. At the gut microbiota level, GSF supplementation modulated α-diversity. Further analysis demonstrated that GSF reshaped the GM profile by preventing the blooming of some taxa, including UBA1819, Akkermansia, and Bacteroides caecimuris, and enriching butyrate-producing bacteria, such as Muribaculaceae and Ruminococcus. These shifts were accompanied by lower acetone and ethyl acetate levels and higher indole levels, which are known to support epithelial barrier integrity and mucosal homeostasis. Conclusions: Overall, GSF mitigates DSS-induced colitis through combined actions on inflammatory signalling, oxidative stress, immune regulation, microbiota composition and microbiota-derived metabolites, supporting its potential as a functional prebiotic ingredient for intestinal health. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, encompasses a continuum from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. This review aimed to synthesize current evidence on how metabolomic, lipidomic, and spatial multi-omic approaches illuminate MASLD pathogenesis and support precision hepatology. Methods: A structured narrative review was conducted through searches of PubMed, Scopus, and Web of Science, complemented by manual screening of key references. Studies were prioritized when they addressed MASLD biology, metabolic rewiring, lipid remodeling, mitochondrial dysfunction, inflammatory and fibrogenic pathways, gut–liver–adipose crosstalk, biomarker development, or therapeutic monitoring. Results: The reviewed evidence identifies MASLD as a systemic metabolic disorder shaped by excess lipid flux, enhanced de novo lipogenesis, impaired mitochondrial adaptation, oxidative and endoplasmic reticulum stress, sterile inflammation, and hepatic stellate-cell activation. Recurrent metabolomic signatures include altered amino acid, fatty acids, bile acid, and microbial co-metabolite pathways. Lipidomic studies consistently implicate depletion of protective polyunsaturated fatty acids, lysophosphatidylcholines, and phosphatidylcholines, in association with accumulation of diacylglycerols and ceramides, in the transition from steatosis to MASH and fibrosis. Emerging spatial and multi-omic analyses further resolve cell-specific metabolic niches involving hepatocytes, macrophages, endothelial cells, and stellate cells. Conclusions: Metabolomics provides a mechanistic and translational bridge between molecular injury, histological progression, and non-invasive risk stratification in MASLD. Future progress requires standardized analytical workflows, longitudinal validation, causal pathway interrogation, and integration with imaging, genetics, microbiome profiling, and treatment-response phenotyping. Clinical implementation will require standardized platforms, transparent metabolite identification, external validation across diverse populations, cost-effectiveness analyses, and regulatory-grade evidence of clinical utility. Full article

Microplastics and nanoplastics (MNPs) have been recognized as ubiquitous emerging global pollutants, which are extensively detectable in diverse environmental media and food matrices. Increasing evidence indicates that the intestine is a primary target of orally ingested MNPs and a critical initiating hub for systemic toxicity. Once ingested orally, MNPs can interact with the intestinal mucus layer and epithelial barrier, induce gut microbiota dysbiosis, remodel bile acid and short-chain fatty acid metabolism, and activate oxidative stress, inflammation, apoptosis, and immune imbalance. These gut-derived disturbances may subsequently propagate adverse signals to distal organs through the gut-liver, gut-brain, gut-kidney, gut-lung, gut-reproductive, and gut-mammary axes. Intestinal barrier dysfunction, endotoxin translocation, abnormal microbial metabolites, and microbiota-derived immune signals constitute common mediating pathways linking local intestinal injury to multi-organ toxicity. In addition, smaller particle size, surface oxidation, environmental aging, bio-corona/plastisphere formation, and co-exposure with other contaminants can further modulate the intensity and specificity of gut-organ axis disruption. Prior reviews are limited to separate analyses of single-organ toxicity or isolated gut-organ pathways. To fill this gap, this work synthesizes contemporary mechanistic and experimental evidence to establish a gut-initiated systemic toxicology framework for MNPs. We differentiate direct particle translocation from gut-derived indirect signaling, evaluate the varying robustness of supporting evidence for each gut-organ axis, and underscore nanoscale biointerface properties as key modulators of MNPs systemic toxic potency. Full article

Gut barrier dysfunction and portal endotoxemia contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression through activation of hepatic inflammatory signaling. Milk-derived extracellular vesicles (EVs) contain bioactive microRNAs and have recently attracted attention as modulators of intestinal homeostasis. This study investigated the effect of bovine milk-derived extracellular vesicles (B-mEVs) in ameliorating MASH by improving intestinal barrier function. C57BL/6J mice fed a choline-deficient amino acid-defined high-fat diet (CDA-HFD) were orally treated with B-mEVs, and therapeutic effects were evaluated. Liver histology, fibrosis, portal lipopolysaccharide (LPS) levels, intestinal permeability, and gut microbiota composition were evaluated. The direct effects of B-mEVs on intestinal barrier function were assessed using palmitic acid-stimulated Caco-2 cells. Small RNA sequencing and microRNA enrichment analyses were performed to characterize B-mEV cargo. B-mEV treatment attenuated hepatic steatosis, inflammation, and fibrosis in CDA-HFD-fed mice and reduced serum aminotransferase levels, portal LPS concentrations, hepatic macrophage accumulation, and hepatic TLR4/NF-κB signaling activation. Meanwhile, B-mEVs restored intestinal tight junction proteins, including ZO-1, occludin, and claudin-1, and improved intestinal permeability in vivo. In Caco-2 cells, B-mEVs attenuated palmitic acid-induced barrier dysfunction and suppressed myosin light chain kinase expression. Gut microbiota analysis revealed partial restoration of Akkermansia abundance after B-mEV administration. Furthermore, to explore the molecular basis of these protective effects, small RNA sequencing demonstrated enrichment of regulatory microRNAs, including let-7a-5p, and pathway analyses identified associations with intestinal barrier and inflammatory signaling pathways. B-mEVs ameliorated CDA-HFD-induced steatohepatitis by restoring intestinal barrier integrity and suppressing gut-derived LPS/TLR4 inflammatory signaling. These findings suggested that milk EVs may represent a novel gut–liver axis-targeted therapeutic strategy for MASH. Full article