Gut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease

Hepatology, Год журнала: 2024, Номер 80(6), С. 1342 - 1371

Опубликована: Май 1, 2024

The growing recognition of the role gut microbiome’s impact on alcohol-associated diseases, especially in liver disease, emphasizes need to understand molecular mechanisms involved governing organ-organ communication identify novel avenues combat diseases. gut-liver axis refers bidirectional and interaction between liver. Intestinal microbiota plays a pivotal maintaining homeostasis within axis, this significant disease. intricate intestine involves multiple cellular components each organ that enable them carry out their physiological functions. In review, we focus approaches understanding how chronic alcohol exposure impacts microbiome individual cells intestine, as well ethanol machinery required for intraorgan interorgan communication.

Язык: Английский

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Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease

eGastroenterology, Год журнала: 2024, Номер 2(4), С. e100104 - e100104

Опубликована: Дек. 1, 2024

Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation well-established key factor, recent evidence highlights critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced injury. This review provides comprehensive analysis complex interactions within hepatic microenvironment ALD. It examines contributions both parenchymal cells, like hepatocytes, non-parenchymal such as stellate Kupffer neutrophils, sinusoidal endothelial driving progression disease. Additionally, we explored involvement mediators, including cytokines, chemokines inflammasomes, which regulate inflammatory responses promote injury fibrosis. A particular focus has been placed on extracellular vesicles (EVs) essential mediators intercellular communication beyond liver. These facilitate transfer signalling molecules, microRNAs proteins, modulate immune responses, fibrogenesis lipid metabolism, thereby influencing progression. Moreover, underscore importance organ-to-organ crosstalk, particularly gut-liver axis, where dysbiosis increased intestinal permeability lead to microbial translocation, exacerbating inflammation. The adipose-liver axis also highlighted, impact adipokines free fatty acids from adipose tissue steatosis inflammation context alcohol consumption.

Язык: Английский

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The role of macrophages in liver fibrosis: composition, heterogeneity, and therapeutic strategies

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Ноя. 20, 2024

Macrophages, the predominant immune cells in liver, are essential for maintaining hepatic homeostasis and responding to liver injury caused by external stressors. The macrophage population is highly heterogeneous plastic, mainly comprised of resident kuffer (KCs), monocyte-derived macrophages (MoMφs), lipid-associated (LAMs), capsular (LCMs). KCs, a macrophages, localized can self-renew through situ proliferation. However, MoMφs recruited from periphery circulation. LAMs self-renewing subgroup near bile duct. While LCMs located capsule derived peripheral monocytes. also involved damage induced various factors. Hepatic exhibit distinct phenotypes functions depending on specific microenvironment liver. KCs critical initiating inflammatory responses after sensing tissue damage, while infiltrated implicated both progression resolution chronic inflammation fibrosis. regulatory function fibrosis has attracted significant interest current research. Numerous literatures have documented that dual impact be categorized into two subtypes based their Ly-6C expression level: with high (referred as hi macrophages) reparative low lo macrophages). conducive occurrence fibrosis, associated degradation extracellular matrix (ECM) regression Given this, play pivotal role occurrence, progression, Based these studies, treatment therapies targeting being studied gradually. This review aims summarize researches composition origin heterogeneity anti-fibrosis therapeutic strategies

Язык: Английский

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Ethanol Disrupts the Protective Crosstalk Between Macrophages and HBV-Infected Hepatocytes

Biomolecules, Год журнала: 2025, Номер 15(1), С. 57 - 57

Опубликована: Янв. 3, 2025

About 296 million people worldwide are living with chronic hepatitis B viral (HBV) infection, and outcomes to end-stage liver diseases potentiated by alcohol. HBV replicates in hepatocytes, but other non-parenchymal cells can sense the virus. In this study, we aimed investigate regulatory effects of macrophages on marker interferon-stimulated genes (ISGs) expressions hepatocytes. This study was performed HBV-replicating HepG2.2.15 human monocyte-derived (MDMs). We found that exposure an acetaldehyde-generating system (AGS) increased RNA, DNA, cccDNA suppressed activation ISGs, APOBEC3G, ISG15, OAS1. Supernatants collected from IFNα-activated MDMs decreased levels induced ISG AGS-treated untreated HepG2.215 cells. These were reversed ethanol mimicked treatment exosome release inhibitor GW4869. conclude exosome-mediated crosstalk between IFN-activated hepatocytes plays a protective role via up-regulation ISGs suppression replication. However, breaks protection.

Язык: Английский

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The Effects of White Wine and Ethanol Consumption on the Proliferative Phase of Repair After a Surgically Induced Myocardial Infarction in Rats

Nutrients, Год журнала: 2025, Номер 17(4), С. 699 - 699

Опубликована: Фев. 15, 2025

Background: Our recent findings, of the highest survival rate animals that consumed moderate amounts white wine for four weeks prior to surgically induced myocardial infarction by ligation left anterior descending artery, prompted us investigate inflammatory aspects post-infarction healing process. In order examine whether effects consumption differ from ethanol, experimental were randomized into three groups: wine, 13% v/v ethanol/water or water-only controls. Methods: Hearts immunohistochemical analysis collected survived 96 h after infarction, no less than 8 mL solution per day and had transmural infarcts comparable sizes. After accounting all above criteria, final number was seven group. Tissue slices stained with a pan-macrophage marker CD68 an anti-inflammatory macrophage CD163 polarization is crucial healing. Immunofluorescent imaging performed on zones surrounding infarcted area detritus: subepicardial, subendocardial two peri-infarct zones. Results: The largest CD163/CD68 ratios volumes alcohol observed in group decreased both ethanol as average amount alcoholic beverage increased. Conclusions: results indicate non-alcoholic constituents contribute its superior favorable modulation inflammation processes relative alone.

Язык: Английский

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Therapeutic potential of elafibranor in alcohol-associated liver disease: Insights into macrophage modulation and fibrosis reduction

World Journal of Biological Chemistry, Год журнала: 2025, Номер 16(1)

Опубликована: Март 5, 2025

Alcohol-associated liver disease (ALD) is a major global health concern, contributing to injury, morbidity, and mortality. Elafibranor (EFN), dual peroxisome proliferator-activated receptor α/δ agonist, has shown promise as therapeutic candidate in preclinical studies. EFN reduces fibrosis by inhibiting lipid accumulation, apoptosis, inflammatory pathways (LPS/TLR4/NF-κB), while enhancing autophagy antioxidant responses. It also improves intestinal barrier function modulates gut microbiota, reducing endotoxin-producing bacteria increasing beneficial species. By strengthening the suppressing pro-inflammatory mediators like tumor necrosis factor-alpha interleukin-6, mitigates hepatic stellate cell activation fibrogenic signaling. Macrophages play central role ALD progression, EFN's ability modulate macrophage activity further highlights its anti-inflammatory properties. This review emphasizes dual-targeted approach, addressing both dysfunctions, distinguishing it from conventional treatments. While results are promising, remains under clinical investigation, with ongoing trials evaluating safety efficacy. Future research should focus on elucidating molecular mechanisms advancing application establish potential human populations. represents novel, comprehensive strategy for management, targeting pathologies.

Язык: Английский

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Immune cell phenotypes as causal factors in liver disease progression revealed by Mendelian randomization

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Апрель 12, 2025

Immune cells are central mediators of the immune response and play critical roles in pathogenesis progression liver diseases. Understanding specific contributions to disease is essential for developing targeted therapeutic strategies. In this study, we employed a two-sample Mendelian randomization (MR) approach explore potential causal relationships between peripheral cell phenotypes diseases, using genetic instrumental variables from large-scale genome-wide association studies (GWAS). Applying inverse variance weighted (IVW) methods, identified that monocyte count(odds ratio (OR) 0.81; 95% confidence interval (CI) 0.74-0.90; P = 5.95 × 10- 5, PFDR 3.57 4), CD3- lymphocyte/lymphocyte (OR 0.59, CI 0.45-0.79; 3.29 4, 5.92 3) SSC-A (Side Scatter Area) on Natural Killer (NK) 0.89, 0.82-0.95; 1.37 3, 0.0396) acted as protective factors against alcoholic disease. Similarly, trait HLA DR++ monocyte/monocyte was associated with lower risk autoimmune hepatitis 0.56, 0.41-0.79; 7.42 0.0475). Conversely, an elevated blood monocytic Myeloid-Derived Suppressor Cells (MDSCs) count higher chronic 1.23, 1.11-1.37; 1.13 1.58 3). levels DR CD14- CD16+ 0.84, 0.78-0.91; 2.07 1.32 conferred cirrhosis liver. hepatic failure, CD39+ resting CD4 regulatory T 0.85, 0.79-0.92; 1.70 5.25 played role CD28+ CD45RA- CD8dim cell/CD8dim 1.14, 1.06-1.22; 2.63 0.0406) exhibited function. Our findings highlight key pathways underscore immunomodulatory targets future interventions. Further research warranted clarify mechanistic underpinnings these associations.

Язык: Английский

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Alcohol-induced gut permeability defect through dysbiosis and enterocytic mitochondrial interference causing pro-inflammatory macrophages in a dose dependent manner

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Апрель 27, 2025

Although toxicity of alcohol toward the intestines and immunity is mentioned, there might be different effect in a low high dose rodent model development using simple SHIRPA binary score night useful. Hence, (6.30 1.26 g/kg/day) were administered for 16 weeks before determination several parameters. As such, peak blood concentration (BAC) approximately at 0.05 0.15%, respectively, 1 h post-administration, which correlated with 1.8 ± 0.8 7.2 0.6, respectively. After wk administration, significant liver injury high-dose was indicated by enzymes, weight, histology score, apoptosis, hepatic accumulation triglyceride (TG) oxidative stress (malondialdehyde; MDA) reduced anti-oxidant (glutathione). Meanwhile, low-dose demonstrated only elevated apoptosis increased TG MDA tissue. Leaky gut from both also FITC-dextran, endotoxemia, serum beta glucan, occludin. However, bacterial abundance (microbiome analysis) feces small bowel alcohol, but not dose, control (increased Alitipes spp. Lachnospiraceae). In conclusion, low- induced leaky gut, while caused dysbiosis damaged mitochondria enhanced glycolysis enterocytes macrophages. more sensitive than to determine alcohol-induced intestinal injury.

Язык: Английский

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Baicalin mitigates alcoholic-associated liver disease via SOCS1-driven reprogramming of macrophages

Chinese Medicine, Год журнала: 2025, Номер 20(1)

Опубликована: Май 13, 2025

Язык: Английский

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Hepatic Proteomic Changes Associated with Liver Injury Caused by Alcohol Consumption in Fpr2−/− Mice

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(18), С. 9807 - 9807

Опубликована: Сен. 11, 2024

Alcohol-associated liver disease (ALD) is a prevalent medical problem with limited effective treatment strategies. Although many biological processes contributing to ALD have been elucidated, complete understanding of the underlying mechanisms still lacking. The current study employed proteomic approach identify hepatic changes resulting from ethanol (EtOH) consumption and genetic ablation formyl peptide receptor 2 (FPR2), G-protein coupled known regulate multiple signaling pathways processes, in mouse model ALD. Since previous research our team demonstrated notable reduction FPR2 protein levels patients alcohol-associated hepatitis (AH), livers

Язык: Английский

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