Search Results (431)

Novel coronavirus (SARS-CoV-2) is highly infectious and pathogenic. Novel coronavirus infection can not only cause respiratory diseases but also lead to multiple organ damage through direct or indirect mechanisms, in which the liver is one of the most frequently affected organs. It has been reported that 15–65% of coronavirus disease 2019 (COVID-19) patients experience liver dysfunction, mainly manifested as mild to moderate elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Severe patients may progress to liver failure, develop hepatic encephalopathy, or have poor coagulation function. The mechanisms underlying this type of liver injury are complex. Pathways—including direct viral infection (via ACE2 receptors), immune-mediated responses (e.g., cytokine storm), ischemic/hypoxic liver damage, thrombosis, oxidative stress, neutrophil extracellular trap formation (NETosis), and the gut–liver axis—remain largely speculative and lack robust clinical causal evidence. In contrast, drug-induced liver injury (DILI) has been established as a well-defined causative factor using the Roussel Uclaf Causality Assessment Method (RUCAM). Treatment should simultaneously consider antiviral therapy and liver protection therapy. This article systematically reviewed the mechanism, clinical diagnosis, treatment, and management strategies of COVID-19-related liver injury and discussed the limitations of current research and the future directions, hoping to provide help for the diagnosis and treatment of such patients. Full article

Cholangiocarcinoma (CCA) is an aggressive malignancy of the biliary tract with rising global incidence and limited treatment options. Its pathogenesis involves a complex interplay of genetic mutations, epigenetic dysregulation, inflammatory signaling, and environmental influences. Emerging evidence highlights the pivotal role of the gut–liver axis and microbiota dysbiosis in shaping biliary homeostasis and disease progression. Alterations in microbial composition disrupt apoptosis and autophagy, two key processes regulating cell survival and death, thereby contributing to tumorigenesis, metastasis, and therapy resistance. Specific taxa, including Enterococcus, Escherichia coli, Pseudomonas, Bifidobacterium, and Bacillus, demonstrate strain-dependent effects, acting either as tumor promoters through genotoxic metabolites and immune evasion or as potential tumor suppressors by inducing apoptosis and immune activation. These findings underscore the context-dependent roles of microbiota in CCA biology. Importantly, microbiota modulation offers novel therapeutic opportunities. Dietary interventions such as probiotics, prebiotics, and nutritional strategies, alongside innovative microbiome-targeted therapies, hold promise for restoring microbial balance, enhancing antitumor immunity, and improving patient outcomes. This review integrates current molecular and microbiological evidence to propose the gut microbiota as both a biomarker and a therapeutic target in CCA, opening avenues for precision medicine approaches in hepatobiliary oncology. Full article

Alcohol-associated liver disease (ALD) includes a spectrum from steatosis and steatohepatitis to cirrhosis and hepatocellular carcinoma driven by oxidative stress, immune activation, and systemic inflammation. Ethanol metabolism through alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P450 2E1 generates reactive oxygen and nitrogen species, leading to mitochondrial dysfunction, hepatocellular injury, and activation of inflammatory and fibrogenic pathways. Beyond hepatic effects, ALD engages the gut–liver–brain axis, where microbial dysbiosis, blood–brain barrier disruption, and neuroinflammation contribute to cognitive impairment and cerebrovascular risk. The emerging concept, metabolic dysfunction-associated steatotic liver disease and increased alcohol intake (MetALD), presents the synergistic impact of alcohol and metabolic comorbidities, enhancing oxidative injury and fibrosis. This review summarizes key mechanisms connecting oxidative stress to multisystem pathology and highlights the need for precision therapies targeting redox imbalance, immune dysregulation, and gut–brain–liver interactions to improve outcomes in ALD and MetALD. Full article

Objectives: Emerging evidence suggests that propolis possesses significant anti-obesity properties. While gut hormones and microbiota are known to play crucial roles in obesity development, the specific mechanisms through which propolis exerts its effects via the gut hormone axis remain poorly characterized. Methods: A high-fat diet (HFD) rat model was established to investigate the regulatory effects of propolis. After 10 weeks of intervention, blood serum, liver, colon tissues, and luminal contents were analyzed for metabolic parameters, gene expression of gut hormones and AMPK pathway markers, microbial community structure, and short-chain fatty acid production. Results: Propolis effectively mitigated HFD-induced metabolic disturbances, including excessive weight gain, adipose tissue accumulation, hyperlipidemia, and hepatic dysfunction. These improvements were associated with significant upregulation of the AMPK pathway. Importantly, propolis enhanced intestinal barrier integrity and differentially modulated gut hormone expression by increasing the mRNA levels of Cck, Gip, and Ghrl, and decreasing Lep and Gcg levels. 16S rRNA sequencing analysis revealed that propolis administration selectively enriched butyrate- and propionate-producing bacterial species. Correlation analysis further identified the Eubacterium brachy group as a pivotal microbial mediator in the propolis-modulated gut microbiota–gut hormone–liver AMPK axis. Conclusions: Our findings establish that propolis ameliorates obesity-related metabolic disorders by orchestrating crosstalk among gut microbiota, enteroendocrine hormones, and hepatic AMPK signaling. These results elucidate a novel mechanistic pathway in rodents; however, their direct translatability to humans requires further clinical investigation. This tripartite axis offers a mechanistic foundation for developing microbiota-targeted anti-obesity therapies. Full article

Background: The gut-liver axis is essential for maintaining liver physiology, with the gut microbiota playing a central role in this bidirectional communication. Recent studies have identified microbiota-derived extracellular vesicles (EVs) as key mediators of inter-organ signaling. This study explored the impact of EVs from two beneficial Escherichia coli strains, the probiotic EcN and the commensal EcoR12, on hepatic metabolism and oxidative stress in healthy neonatal rats. Methods: EVs were administered orally during the first 16 days of life, and blood and liver samples were collected on days 8 and 16. Results: The results demonstrated that EVs significantly reduced intestinal permeability, as evidenced by decreased plasma zonulin levels. In the liver, EVs enhanced redox homeostasis by downregulating CYP2E1 and upregulating key antioxidant genes (SOD1, CAT, GPX). Furthermore, the treatment shifted liver metabolism toward an anti-lipogenic profile by inducing fatty acid oxidation genes (PPARA, CPT1A) and suppressing genes involved in de novo lipogenesis (SREBP1C, ACC1, FASN, CNR1). Importantly, markers of hepatic inflammation remained unchanged, indicating the safety of the intervention. In vitro experiments using human HepG2 cells supported these findings, further validating the antioxidant and metabolic effects of the EVs. Conclusions: Our results underscore the role of microbiota-derived EVs as important mediators of hepatic metabolic programming in healthy individuals via the gut-liver axis and highlight their potential as therapeutic postbiotic agents for management of fatty liver diseases. Full article

Inter-organ communication plays a vital role in the pathogenesis of neurodegenerative diseases (ND), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Emerging research highlights the involvement of the gut–brain axis, immune system, and peripheral metabolic systems in modulating neuroinflammation, protein misfolding, and neuronal dysfunction by releasing cytokines, adipokines, growth factors, and other soluble factors, which in turn affect neuronal health and systemic inflammation. This review explores the complex bidirectional interactions between the brain and peripheral organs, including the gut, adipose tissue, liver, muscle, bone and immune system. Notably, the gut microbiome’s role in neurodegenerative diseases through the gut–brain axis, the impact of adipose tissue in inflammation and metabolic regulation, and the muscle–brain axis with its neuroprotective myokines are also discussed. Additionally, we examine the neuro-immune axis, which mediates inflammatory responses and exacerbates neurodegeneration, and liver–brain axis that is implicated in regulating neuroinflammation and promoting disease progression. Dysregulation of inter-organ pathways contributes to the systemic manifestations of neurodegenerative diseases, offering insights into both potential biomarkers and therapeutic targets, and, in turn, promising strategies for preventing, diagnosing, and treating neurodegenerative diseases. Full article

The expression “lung–gut–liver axis” refers to the interconnected processes occurring in the lungs, gastrointestinal tract, and liver, particularly in relation to immune function, microbial regulation, and metabolic responses. Over the past decade, growing concern has emerged regarding the detrimental impact of air pollution on liver disease. Air pollutants, including particulate matter (PM) and chemical gases such as nitrogen oxides (NOx), can influence the microbiome in the lungs and gut by generating reactive oxygen species (ROS), which induce oxidative stress and local inflammation. This redox imbalance leads to the production of altered secondary microbial metabolites, potentially disrupting both the alveolar–capillary and gut barriers. Under these conditions, microbes and their metabolites can translocate to the liver, triggering inflammation and contributing to liver diseases, particularly metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and hepatocellular carcinoma (HCC). This manuscript aims to review recent findings on the impact of air pollution on liver disease pathogenesis, exploring the molecular, genetic, and microbiome-related mechanisms underlying lung–gut–liver interactions, providing insights into potential strategies to prevent or mitigate liver disease progression. Full article

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by pathogenic mutations in the nuclear TYMP gene, which encodes the cytosolic enzyme thymidine phosphorylase. In addition to the systemic accumulation of thymidine and deoxyuridine, several case studies have reported abnormalities in a range of other metabolites in patients with MNGIE. Since metabolites are intermediates or end-products of numerous biochemical reactions, they serve as highly informative indicators of an organism’s metabolic activity. This study aimed to perform an untargeted metabolomic profiling to determine whether individuals with MNGIE exhibit a distinct plasma metabolic signature compared to 15 age- and sex-matched healthy controls. Metabolites were profiled using Ultra-High-Performance Liquid Chromatography–Mass Spectrometry (UHPLC-MS). A total of 160 metabolites were found to be significantly upregulated and 260 downregulated in patients with MNGIE. KEGG pathway enrichment analysis revealed disruptions in 20 metabolic pathways, with arachidonic acid metabolism and bile acid biosynthesis being the most significantly upregulated. Univariate receiver operating characteristic (ROC) curve analyses identified 23 individual metabolites with diagnostic potential, each showing an area under the curve (AUC) ≥ 0.80. We propose that an impaired resolution of inflammation contributes to a chronic inflammatory state in MNGIE, potentially driving disease progression. Additionally, we suggest that the gut–liver axis plays a central role in MNGIE pathophysiology, with hepatic function being bidirectionally influenced by gut-derived factors. Full article

Widespread contamination of deoxynivalenol (DON) in cereals and feed threatens global food safety. This study investigated the effects of Chlorogenic acid (CGA) and VX765 on DON-induced enterohepatic injury. A total of 48 female mice were divided into four groups: control (normal saline), DON (1 mg/kg.bw), CGA (100 mg/kg.bw CGA + 1 mg/kg.bw DON), and VX765 (100 mg/kg.bw VX765 + 1 mg/kg.bw DON). After 28-day gavage period, the results showed that CGA and VX765 reduced DON-induced intestinal barrier damage. Metabolomics data revealed that CGA and VX765 restored cecal microbiota structure and alleviated DON-induced hepatic injury and lipid metabolic disorders by reshaping intestinal microbiota. Retrograde endocannabinoid signaling was identified as a critical pathway for cecal microbial metabolism and hepatic lipid regulation mediated by CGA and VX765. Additionally, CGA and VX765 reversed the upregulation of IMPA, CDS2, DGKA, NDUFS8, and MAPK1 mRNA and protein expression levels induced by DON via the microbiota-gut-liver axis. Full article

Background/Objectives: This study aimed to investigate the effects of long-term aerobic exercise on high-fat diet (HFD)-induced hepatic steatosis and its underlying enterohepatic communication mechanisms. Methods: C57BL/6J mice were divided into four groups: normal-diet with sedentary (ND-SED), normal-diet with exercise (ND-EXE), HFD with sedentary (HFD-SED), and HFD with exercise (HFD-EXE). After 16 weeks of HFD feeding, ND-EXE and HFD-EXE groups underwent an 8-week aerobic exercise intervention. Hepatic lipid accumulation was assessed via histology and triglyceride (TG) quantification. Liver function and glucose tolerance were evaluated. Gut microbiota composition (16S rRNA sequencing), hepatic bile acid profiles (LC-MS metabolomics), and gene expression were analyzed. Results: HFD induced hepatic steatosis, glucose intolerance, and liver injury in mice, all of which were ameliorated by exercise. Compared to HFD-SED mice, which exhibited impaired gut microbiota diversity, exercise restored key genera such as Faecalibaculum, and Turicibacter. Functional analysis revealed that exercise modulated microbiota shifts in lipid metabolism and secondary bile acid biosynthesis. HFD-EXE mice displayed altered hepatic bile acid composition, characterized by increased tauroursodeoxycholic acid (TUDCA) and reduced taurohyodeoxycholic acid (THDCA). Notably, TUDCA levels correlated with Turicibacter abundance, while deoxycholic acid (DCA) was associated with Faecalibaculum, independent of precursor availability. Exercise also suppressed hepatic endoplasmic reticulum (ER) stress and downregulated lipogenic genes via the inositol-requiring enzyme 1 alpha (IRE1α)- spliced X-box binding protein 1 (Xbp1s) pathway, while concurrently activating farnesoid X receptor (FXR) signaling to enhance fatty acid oxidation through the FXR-short heterodimer partner (SHP) related to hepatic secondary bile acid abundance change. Conclusions: The beneficial effect of long-term aerobic exercise on high-fat diet-induced hepatic steatosis in mice is potentially mediated through structural changes in the gut microbiota, which influence the abundance of hepatic secondary bile acids (TUDCA, DCA) and subsequently regulate the expression of genes involved in lipid metabolism. Full article

The liver and gut play a central role in modulating bile acid metabolism. Our recent study found that supplementation with sodium butyrate (NaB) from microbiota might slow diabetes progression and ameliorate liver function in diabetic mice. The role of NaB in the homeostasis of mitochondrial energy metabolism and bile acid metabolism needs to be investigated further, so this study was conducted by us. We used an ELISA kit to detect biochemical indicators related to mice; HE and PAS were used to stain and analyze tissues; CCK8 was used to detect cell viability; and WB was used to detect related indicators. We found here that NaB administration enormously reduced liver hypertrophy and steatosis in diabetic mice, improved liver and gut function and the release of inflammatory factors in diabetic mice, and ameliorated mitochondrial function both in vitro and in vivo. NaB incubation significantly increased bile acid metabolism-related receptors under diabetic conditions; the intracellular content of enzymes related to liver function was elevated within liver cells. Glucose transport proteins GLUT2 and NaB receptor GPR43 were upregulated by NaB on the cell membrane. The actuation of the intracellular signaling proteins PI3K, AKT, and GSK3 was inhibited by NaB under diabetic conditions. The present study proved that the microbiota metabolite NaB has positive effects on bile acid metabolic homeostasis by promoting mitochondrial energy metabolism in enterocytes and the liver, and the GPR43-PI3K-AKT-GSK3 signaling pathway should contribute to this effect. Full article

Objectives: Disruption of gut–liver axis homeostasis is a hallmark of metabolic and toxic stress. This study aimed to evaluate the combined effects of high-fat diet (HFD), aflatoxin B1 (AFB1), and exogenous isoleucine supplementation on immunometabolic function under nutritional and toxic stress. Methods: Two-phase murine experiments assessed: (1) HFD and AFB1 effects individually and combined; and (2) dose-dependent isoleucine responses (25/50/100 mg/kg) across control, HFD, and HFD + AFB1 backgrounds. Results: HFD significantly impaired liver function, promoted Th17-mediated inflammation, and induced gut dysbiosis, while AFB1 alone exerted minimal effects. Their combination synergistically exacerbated hepatic steatosis, intestinal barrier disruption, and inflammatory responses. Fecal metabolomics identified elevated isoleucine as a potential inflammatory biomarker. Under HFD, isoleucine (50 mg/kg) amplified inflammation and oxidative stress. Remarkably, under HFD + AFB1, moderate/high-dose isoleucine reduced hepatic lipid deposition and triglycerides despite persistent intestinal damage, demonstrating context-dependent effects. Conclusions: HFD and AFB1 synergistically disrupt gut–liver axis integrity through immunometabolic mechanisms. Isoleucine supplementation exhibits dual-modulatory effects, exacerbating damage under nutritional stress while partially mitigating hepatic lipid accumulation under combined toxic-nutritional stress, highlighting the critical importance of environmental context in amino acid interventions. Full article

Hepatic oxidative stress is a key driver in liver injury pathogenesis, with D-galactose (D-gal) modeling serving as an established inducer of accelerated oxidative damage. Silibinin (SLB), a flavonolignan from milk thistle, shows therapeutic promise through potent antioxidant activity and gut–liver axis modulation. This study investigated whether the hepatoprotective effect of SLB against oxidative stress depends on gut microbiota regulation. Using mouse models with gut microbiota ablation by oral antibiotics or direct oxidative stress induction by D-gal (150 mg/kg), SLB treatment (200 mg/kg) was administered. The protective mechanisms were evaluated through the Nrf2/ARE pathway, target gene expression, gut microbiota profiling, and cecal metabolomics. Results demonstrated that SLB significantly alleviated D-gal-induced hepatic oxidative stress (e.g., reduced MDA by 33.3%), but this protection was markedly weakened after antibiotic-induced microbiota depletion (e.g., a loss of efficacy exceeding 50%). Integrated omics revealed that antibiotics caused a severe reduction in unclassified_Muribaculaceae (a butyrate producer, decreased by 80%), impairing butyrate-mediated Nrf2/Keap1 activation. Simultaneously, the absence of Parabacteroides led to accumulated primary bile acids and inhibited secondary bile acid production (e.g., taurochenodeoxycholate reduced by 75%), further disrupting redox homeostasis. Conclusion: Silibinin’s mitigation of hepatic oxidative stress is gut microbiota-dependent, highlighting the therapeutic potential of microbiota-targeted antioxidant strategies for oxidative stress-related pathologies. Full article

Irritable Bowel Syndrome (IBS) and Metabolic dysfunction-associated fatty liver disease (MAFLD) have traditionally been viewed as disorders of distinct organ systems. IBS is a gut–brain axis disorder characterized by abdominal pain, altered bowel habits, and psychological comorbidities. MAFLD, recently redefined to emphasize its metabolic underpinnings, is the hepatic manifestation of systemic metabolic dysfunction. Growing evidence suggests that these conditions share overlapping pathophysiological mechanisms linked through disruption of the gut–liver–brain axis (GLBA), including psychological stress, gut dysbiosis, impaired intestinal permeability, systemic inflammation, and altered neuroendocrine signaling. Neuroimaging studies further reveal functional alterations in brain regions responsible for interoception, emotional regulation, and stress responsiveness in both disorders. This narrative review explores how psychological distress influences the onset and progression of IBS and MAFLD via GLBA dysfunction and stress-induced epigenetic reprogramming. A targeted literature search of major biomedical databases, supplemented by manual screening, identified relevant observational, clinical, neuroimaging, and molecular studies. Findings indicate that chronic psychological distress activates the hypothalamic–pituitary–adrenal (HPA) axis, elevates cortisol, disrupts gut microbiota, and reduces vagal tone; amplifying intestinal permeability and microbial translocation. These changes promote hepatic inflammation and gastrointestinal symptoms. Stress-related epigenetic modifications further impair GLBA communication, while psychological and lifestyle interventions may reverse some of these molecular imprints. Recognizing the shared neuromodulation and epigenetic mechanisms that link IBS and MAFLD opens promising avenues for integrated therapeutic strategies targeting the GLBA to improve outcomes across both conditions. Full article

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) encompasses a spectrum of liver conditions and involves gut–liver axis crosstalk. We aimed to evaluate whether oral vancomycin modifies liver injury and the cecal microbiota in a methionine–choline-deficient (MCD) diet model of NASH. Male C57BL/6J mice (n = 28) were block-randomized to four groups (n = 7 each) for 10 weeks: standard diet (STD); MCD diet; STD + vancomycin (VANC); and MCD + VANC (2 mg/mouse ≈ 50 mg/kg, every 72 h). After 10 weeks, liver tissues were analyzed for histological changes, cytokine levels [interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor beta 1 (TGF-β1)], and immunohistochemical markers [ubiquitin and cytokeratin 18 (CK18)]. Cecal microbiota composition was evaluated with 16S ribosomal RNA (rRNA) sequencing. The MCD reproduced key NASH features (macrovesicular steatosis, lobular inflammation). Vancomycin shifted steatosis toward a microvesicular pattern and reduced hepatocyte injury: CK18 and ubiquitin immunoreactivity were decreased in MCD + VANC vs. MCD, and hepatic IL-8 and TGF-β1 levels were lower in MCD + VANC vs. STD. Taxonomically, STD mice had Lactobacillus-rich microbiota. The MCD diet alone reduced alpha diversity (α-diversity), modestly lowered Firmicutes and increased Desulfobacterota/Fusobacteriota. Vancomycin alone caused a much larger collapse in richness, depleting Gram-positive commensals and promoting blooms of Escherichia–Shigella, Klebsiella, Parabacteroides, and Akkermansia. In the MCD + VANC group, vancomycin profoundly remodeled the microbiota, eliminating key commensals (e.g., Lactobacillus) and enriching Desulfobacterota, Fusobacteriota, and Campylobacterota. Oral vancomycin in the MCD model of NASH improved liver injury markers and altered steatosis morphology, but concurrently reprogrammed the gut into a low-diversity, pathobiont-enriched ecosystem with near-loss of Lactobacillus. These findings highlight a therapeutic trade-off—hepatic benefit accompanied by microbiome cost—that should guide microbiota-targeted strategies for NAFLD/NASH. Full article