Impacts of smoking on alcoholic liver disease: a nationwide cohort study.

Objectives: Smoking is a preventable risk factor for morbidity and mortality in patients with liver disease. This study aims to explore the additional risks of smoking in the development of alcoholic liver disease (ALD), cirrhosis, and hepatocellular carcinoma (HCC) in high-risk drinkers. Methods: Data from the National Health Insurance Service, including claims and health check-up information spanning 2011 to 2017, were used. The overall alcohol consumption was calculated, and ALD was defined based on ICD-10 codes. High-risk drinking was defined as 7 or more drinks for men and 5 or more for women, twice weekly. Half of the high-risk drinkers were smokers, decreasing in men but stable at 20% for women. Results: ALD prevalence was 0.97% in high-risk drinkers and 1.09% in high-risk drinkers who smoked, higher than 0.16% in social drinkers (p < 0.001). ALD incidence over 3-years was highest in high-risk drinkers who smoked (2.35%), followed by high-risk drinkers (2.03%) and social drinkers (0.35%) (p < 0.001). Cirrhosis and HCC followed similar patterns, with prevalence and incidence was highest in drinkers who smoked. 3-year mortality was 0.65% in high-risk drinkers who smoked, compared to 0.50% in high-risk drinkers and 0.24% in social drinkers (p < 0.001). Smoking increased the incidence of ALD, cirrhosis, and HCC by 1.32, 1.53, and 1.53 times, respectively (all p < 0.001). Gender-specific analysis revealed higher risk ratios (RR) for women in ALD, alcoholic cirrhosis, and HCC, particularly among high-risk drinkers who smoked. Women showed significantly increased RR in ALD (6.08 to 12.38) compared to men (4.18 to 4.40), and similar trends were observed for cirrhosis and HCC. Conclusion: Smoking significantly heightens the risk of ALD, cirrhosis, and HCC, especially in women, among high-risk drinkers. This emphasizes the importance of smoking cessation, particularly for female patients with ALD.

Fatty acid synthesis is indispensable for Kupffer cells to eliminate bacteria in ALD progression.

BACKGROUND: Dysregulated fatty acid metabolism is closely linked to the development of alcohol-associated liver disease (ALD). KCs, which are resident macrophages in the liver, play a critical role in ALD pathogenesis. However, the effect of alcohol on fatty acid metabolism in KCs remains poorly understood. The current study aims to investigate fatty acid metabolism in KCs and its potential effect on ALD development. METHODS: Wild-type C57BL/6 mice were fed a Lieber-DeCarli ethanol liquid diet for 3 days. Then, the liver injury and levels of intrahepatic bacteria were assessed. Next, we investigated the effects and underlying mechanisms of ethanol exposure on fatty acid metabolism and the phagocytosis of KCs, both in vivo and in vitro. Finally, we generated KCs-specific Fasn knockout and overexpression mice to evaluate the impact of FASN on the phagocytosis of KCs and ethanol-induced liver injury. RESULTS: Using Bodipy493/503 to stain intracellular neutral lipids, we found significantly reduced lipid levels in KCs from mice fed an alcohol-containing diet for 3 days and in RAW264.7 macrophages exposed to ethanol. Mechanistically, alcohol exposure suppressed sterol regulatory element-binding protein 1 transcriptional activity, thereby inhibiting fatty acid synthase (FASN)-mediated de novo lipogenesis in macrophages both in vitro and in vivo. We show that genetic ablation and pharmacologic inhibition of FASN significantly impaired KC's ability to take up and eliminate bacteria. Conversely, KCs-specific Fasn overexpression reverses the impairment of macrophage phagocytosis caused by alcohol exposure. We also revealed that KCs-specific Fasn knockout augmented KCs apoptosis and exacerbated liver injury in mice fed an alcohol-containing diet for 3 days. CONCLUSIONS: Our findings indicate the crucial role of de novo lipogenesis in maintaining effective KCs phagocytosis and suggest a therapeutic target for ALD based on fatty acid synthesis in KCs.

Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease.

BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM: To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS: ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS: The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and ß-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION: EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

In vivo Bruton's tyrosine kinase inhibition attenuates alcohol-associated liver disease by regulating CD84-mediated granulopoiesis.

Severe alcohol-associated hepatitis (AH) is a life-threatening form of alcohol-associated liver disease. Liver neutrophil infiltration is a hallmark of AH, yet the effects of alcohol on neutrophil functions remain elusive. Identifying therapeutic targets to reduce neutrophil-mediated liver damage is essential. Bruton's tyrosine kinase (BTK) plays an important role in neutrophil development and function; however, the role of BTK in AH is unknown. Using RNA sequencing of circulating neutrophils, we found an increase in Btk expression (P = 0.05) and phosphorylated BTK (pBTK) in patients with AH compared with healthy controls. In vitro, physiologically relevant doses of alcohol resulted in a rapid, TLR4-mediated induction of pBTK in neutrophils. In a preclinical model of AH, administration of a small-molecule BTK inhibitor (evobrutinib) or myeloid-specific Btk knockout decreased proinflammatory cytokines and attenuated neutrophil-mediated liver damage. We found that pBTK was essential for alcohol-induced bone marrow granulopoiesis and liver neutrophil infiltration. In vivo, BTK inhibition or myeloid-specific Btk knockout reduced granulopoiesis, circulating neutrophils, liver neutrophil infiltration, and liver damage in a mouse model of AH. Mechanistically, using liquid chromatography-tandem mass spectrometry, we identified CD84 as a kinase target of BTK, which is involved in granulopoiesis. In vitro, CD84 promoted alcohol-induced interleukin-1ß and tumor necrosis factor-α in primary human neutrophils, which was inhibited by CD84-blocking antibody treatment. Our findings define the role of BTK and CD84 in regulating neutrophil inflammation and granulopoiesis, with potential therapeutic implications in AH.

Enhanced In Vitro Recapitulation of In Vivo Liver Regeneration by Co-Culturing Hepatocyte Organoids with Adipose-Derived Mesenchymal Stem Cells, Alleviating Steatosis and Apoptosis in Acute Alcoholic Liver Injury.

Hepatocyte organoids (HOs) have superior hepatic functions to cholangiocyte-derived organoids but suffer from shorter lifespans. To counteract this, we co-cultured pig HOs with adipose-derived mesenchymal stem cells (A-MSCs) and performed transcriptome analysis. The results revealed that A-MSCs enhanced the collagen synthesis pathways, which are crucial for maintaining the three-dimensional structure and extracellular matrix synthesis of the organoids. A-MSCs also increased the expression of liver progenitor cell markers (KRT7, SPP1, LGR5+, and TERT). To explore HOs as a liver disease model, we exposed them to alcohol to create an alcoholic liver injury (ALI) model. The co-culture of HOs with A-MSCs inhibited the apoptosis of hepatocytes and reduced lipid accumulation of HOs. Furthermore, varying ethanol concentrations (0-400 mM) and single-versus-daily exposure to HOs showed that daily exposure significantly increased the level of PLIN2, a lipid storage marker, while decreasing CYP2E1 and increasing CYP1A2 levels, suggesting that CYP1A2 may play a critical role in alcohol detoxification during short-term exposure. Moreover, daily alcohol exposure led to excessive lipid accumulation and nuclear fragmentation in HOs cultured alone. These findings indicate that HOs mimic in vivo liver regeneration, establishing them as a valuable model for studying liver diseases, such as ALI.

Diet modifies the association between alcohol consumption and severe alcohol-related liver disease incidence.

It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption.

Cocaine-derived hippuric acid activates mtDNA-STING signaling in alcoholic liver disease: Implications for alcohol and cocaine co-abuse.

The simultaneous abuse of alcohol-cocaine is known to cause stronger and more unpredictable cellular damage in the liver, heart, and brain. However, the mechanistic crosstalk between cocaine and alcohol in liver injury remains unclear. The findings revealed cocaine-induced liver injury and inflammation in both marmosets and mice. Of note, co-administration of cocaine and ethanol in mice causes more severe liver damage than individual treatment. The metabolomic analysis confirmed that hippuric acid (HA) is the most abundant metabolite in marmoset serum after cocaine consumption and that is formed in primary marmoset hepatocytes. HA, a metabolite of cocaine, increases mitochondrial DNA leakage and subsequently increases the production of proinflammatory factors via STING signaling in Kupffer cells (KCs). In addition, conditioned media of cocaine-treated KC induced hepatocellular necrosis via alcohol-induced TNFR1. Finally, disruption of STING signaling in vivo ameliorated co-administration of alcohol- and cocaine-induced liver damage and inflammation. These findings postulate intervention of HA-STING-TNFR1 axis as a novel strategy for treatment of alcohol- and cocaine-induced excessive liver damage.

Alcohol- and Low-Iron Induced Changes in Antioxidant and Energy Metabolism Associated with Protein Lys Acetylation.

Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.

The alleviative effects of viable and inactive Lactobacillus paracasei CCFM1120 against alcoholic liver disease via modulation of gut microbiota and the Nrf2/HO-1 and TLR4/MyD88/NF-κB pathways.

Probiotics can alleviate alcoholic liver disease. However, whether inactive counterparts can produce similar outcomes requires further investigation. We investigated the effects of viable (V) and dead (D) Lactobacillus paracasei CCFM1120 on alcohol-induced ALD mice. The results showed that CCFM1120V and D ameliorated the disease symptoms and intestinal injury. Specifically, these interventions strengthened the intestinal barrier, as evidenced by the increased expression of ZO-1 (zonula occludens 1), occludin, and claudin-1 in the colon and the restored ileal microstructure, including the villi and crypts. In addition, they enhanced the antioxidant capacity of the liver by reducing the production of malondialdehyde and increasing the levels of glutathione and superoxide dismutase. The activation of Nrf2 and HO-1 may be responsible for recovering the antioxidant capacity. Interventions can decrease mouse TNF-α, IL-6 and IL-1ß content in serum, probably through the TLR4/MyD88/NF-κB pathway. Furthermore, they possess the ability to restore the quantities of bacteria responsible for producing butyric acid, such as Lactobacillus, Blautia, Bifidobacterium, Ruminococcaceae, Faecalibaculum and Lachnospiraceae. Taken together, CCFM1120V and D apparently can modify the composition of the gut microbiota, foster the gastrointestinal equilibrium, fortify the intestinal barrier, augment the antioxidant capacity of the liver, and effectively shield it from ethanol-induced injury.

Intestinal microbiota homeostasis analysis in riboflavin-treated alcoholic liver disease.

Alcoholic liver disease (ALD) is a disease with high incidence, limited therapies, and poor prognosis. The present study aims to investigate the effect of riboflavin on ALD and explore its potential therapeutic mechanisms. C57BL/6 mice were divided into the control, alcohol, and alcohol+ riboflavin groups. 16S rRNA-seq and RNA-seq analysis were utilized to analyze the polymorphism of intestinal microbiota and the transcriptome heterogeneity respectively. KEGG and GO enrichment analysis were performed. CIBERSORTx was applied to evaluate the immune cell infiltration level. Publicly available transcriptome data of ALD was enrolled and combined with the RNA-seq data to identify the immune subtypes of ALD. Pathological and histology analysis demonstrated that riboflavin reversed the progression of ALD. 16S rRNA-seq results showed that riboflavin could regulate alcohol-induced intestinal microbiota alteration. Intestinal microbiota polymorphism analysis indicated that VLIDP may contribute to the progression of ALD. Based on the VLIDP pathway, two subtypes were identified. Immune microenvironment analysis indicated that the upregulated inflammatory factors may be important regulators of ALD. In conclusion, intestinal microbiota homeostasis was associated with the protective effect of riboflavin against ALD, which was likely mediated by modulating inflammatory cell infiltration. Riboflavin emerges as a promising therapeutic candidate for the management of ALD.

IFN-ß Overexpressing Adipose-Derived Mesenchymal Stem Cells Mitigate Alcohol-Induced Liver Damage and Gut Permeability.

Alcoholic liver disease (ALD) is a form of hepatic inflammation. ALD is mediated by gut leakiness. This study evaluates the anti-inflammatory effects of ASCs overexpressing interferon-beta (ASC-IFN-ß) on binge alcohol-induced liver injury and intestinal permeability. In vitro, ASCs were transfected with a non-viral vector carrying the human IFN-ß gene, which promoted hepatocyte growth factor (HGF) secretion in the cells. To assess the potential effects of ASC-IFN-ß, C57BL/6 mice were treated with three oral doses of binge alcohol and were administered intraperitoneal injections of ASC-IFN-ß. Mice treated with binge alcohol and administered ASC-IFN-ß showed reduced liver injury and inflammation compared to those administered a control ASC. Analysis of intestinal tissue from ethanol-treated mice administered ASC-IFN-ß also indicated decreased inflammation. Additionally, fecal albumin, blood endotoxin, and bacterial colony levels were reduced, indicating less gut leakiness in the binge alcohol-exposed mice. Treatment with HGF, but not IFN-ß or TRAIL, mitigated the ethanol-induced down-regulation of cell death and permeability in Caco-2 cells. These results demonstrate that ASCs transfected with a non-viral vector to induce IFN-ß overexpression have protective effects against binge alcohol-mediated liver injury and gut leakiness via HGF.

Bacteroides acidifaciens drives a liver detox program.

Alcohol-associated liver disease is a leading cause of chronic liver conditions, yet there are limited effective therapies. In this issue of Cell Host & Microbe, Shen et al. demonstrate that soluble dietary fiber enhances intestinal Bacteroides acidifaciens, which ameliorates alcohol-associated liver injury in mice by activating hepatic ornithine aminotransferase.

Liver injury protection of Artemisia stechmanniana besser through PI3K/AKT pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia stechmanniana Besser, one of the most prevalent botanical medicines in Chinese, has been traditionally used for hepatitis treatment. However, the bioactive components and pharmacological mechanism on alcohol-induced liver injury remains unclear. AIM OF THE STUDY: To investigate the effect of A. stechmanniana on alcohol-induced liver damage, and further explore its mechanism. MATERIALS AND METHODS: Phytochemical isolation and structural identification were used to determine the chemical constituents of A. stechmanniana. Then, the alcohol-induced liver damage animal and cell model were established to evaluate its hepato-protective potential. Network pharmacology, molecular docking and bioinformatics were integrated to explore the mechanism and then the prediction was further supported by experiments. Moreover, both compounds were subjected to ADMET prediction through relevant databases. RESULTS: 28 compounds were isolated from the most bioactive fraction, ethyl acetate extract A. stechmanniana, in which five compounds (abietic acid, oplopanone, oplodiol, hydroxydavanone, linoleic acid) could attenuate mice livers damage caused by alcohol intragastration, reduce the degree of oxidative stress, and serum AST and ALT, respectively. Furthermore, abietic acid and hydroxydavanone exhibited best protective effect against alcohol-stimulated L-O2 cells injury among five bioactive compounds. Network pharmacology and bioinformatics analysis suggested that abietic acid and hydroxydavanone exhibiting drug likeliness characteristics, were the principal active compounds acting on liver injury treatment, primarily impacting to cell proliferation, oxidative stress and inflammation-related PI3K-AKT signaling pathways. Both of them displayed strong binding energies with five target proteins (HRAS, HSP90AA1, AKT1, CDK2, NF-κB p65) via molecular docking. Western blotting results further supported the predication with up-regulation of protein expressions of CDK2, and down-regulation of HRAS, HSP90AA1, AKT1, NF-κB p65 by abietic acid and hydroxydavanone. CONCLUSION: Alcohol-induced liver injury protection by A. stechmanniana was verified in vivo and in vitro expanded its traditional use, and its two major bioactive compounds, abietic acid and hydroxydavanone exerted hepatoprotective effect through the regulation of PI3K-AKT signaling pathway.

Apolipoprotein H deficiency exacerbates alcohol-induced liver injury via gut Dysbiosis and altered bile acid metabolism.

BACKGROUND: APOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear. METHODS: C57BL/6 WT and ApoH-/- mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed. RESULTS: ApoH-/- mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH-/- mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH-/- mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism. CONCLUSION: APOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.

A protective mechanism of heat inactivation to enhance Levilactobacillus brevis PDD-2 against alcohol-induced chronic liver disease based on proteomic analysis.

A proteomics-based analysis of the effect of heat inactivation on the alleviation of alcoholic liver disease (ALD) using Levilactobacillus brevis PDD-2 is presented, aimed at exploring the potential and mechanisms of postbiotic elements prepared through heat inactivation in the treatment of ALD. It was found that L. brevis PDD-2 and its postbiotic (heat-inactivated L. brevis PDD-2) alleviate chronic ALD via the gut-liver axis. In particular, heat-inactivated L. brevis PDD-2 significantly increased the relative abundance of Erysipelotrichaceae and better facilitated the oxidative stress balance in the liver. The tandem mass tag (TMT)-based quantitative proteomics technique analyses revealed that heat-inactivated L. brevis PDD-2 was associated with up-regulated expression levels of proteins related to the redox system, cellular metabolism, amino acid and oligopeptide transport, and surface proteins with immunomodulatory capacity. These findings provide a theoretical basis for developing novel therapeutic strategies and lay a solid foundation for further revealing its exhaustive mechanisms.

Capsaicin alleviates acute alcohol-induced pyroptosis by activating ESCRT-III-dependent cell membrane repair in hepatocytes.

Capsaicin (CAP), the active ingredient in hot chilli peppers, has anti-inflammatory and hepatoprotection effects. Acute alcoholic liver injury (AALI) is liver damage caused by acute alcohol abuse, which can lead to severe liver lesions and even be life-threatening. Pyroptosis is inflammation-related programmed cell death characterized by membrane rupture and plays a key role in AALI. The endosomal sorting complexes required for transport (ESCRT) proteins can gather at damaged areas of the membrane to facilitate the process of sealing the membrane. In this study, we found that CAP could relieve acute alcohol-induced pyroptosis of hepatocytes in vitro and in vivo. Mechanically, we found that CAP could alleviate acute alcohol-induced pyroptosis by activating the ESCRT-III-dependent membrane repair machinery. Furthermore, the data showed that CAP induced ESCRT-III protein expression by activating transient receptor potential vanilloid member 1 (TRPV1) on the cell membrane and Ca2+ influx. TRPV1 inhibitor capsazepine (CPZ) inhibited the relief effect of CAP on acute alcohol-induced pyroptosis. Overall, these results showed that CAP might activate ESCRT-III-dependent membrane repair machinery through Ca2+ influx, which is regulated by TRPV1 calcium channels, therefore mitigating acute alcohol-induced pyroptosis. Our research provides a new perspective on a naturally active food product to promote cell repair and relieve AALI.

Preparation of Dendrobium officinale Polysaccharide by Lactic Acid Bacterium Fermentation and Its Protective Mechanism against Alcoholic Liver Damage in Mice.

Dendrobium officinale polysaccharide (DP) was prepared with lactic acid bacterium fermentation to overcome the large molecular weight and complex structure of traditional DP for improving its functional activity and application range in this work. The structure was analyzed, and then the functional activity was evaluated using a mouse model of alcoholic liver damage. The monosaccharide compositions were composed of four monosaccharides: arabinose (0.13%), galactose (0.50%), glucose (24.38%), and mannose (74.98%) with a molecular weight of 2.13 kDa. The connection types of glycosidic bonds in fermented D. officinale (KFDP) were →4)-ß-D-Manp(1→, →4)-ß-Glcp(1→, ß-D-Manp(1→, and ß-D-Glcp(1→. KFDP exhibited an excellent protective effect on alcoholic-induced liver damage at a dose of 80 mg/kg compared with polysaccharide separated and purified from D. officinale without fermentation (KDP), which increased the activity of GSH, GSH-Px, and GR and decreased the content of MDA, AST, T-AOC, and ALT, as well as regulated the level of IL-6, TNF-α, and IL-1ß to maintain the normal functional structure of hepatocytes and retard the apoptosis rate of hepatocytes. The results proved that fermentation degradation is beneficial to improving the biological activity of polysaccharides. The potential mechanism of KFDP in protecting alcoholic liver damage was inhibiting the expression of miRNA-150-5p and targeting to promote the expression of Pik3r1. This study provides an important basis for the development of functional foods.

Gut microbiota-based machine-learning signature for the diagnosis of alcohol-associated and metabolic dysfunction-associated steatotic liver disease.

Alcoholic-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) show a high prevalence rate worldwide. As gut microbiota represents current state of ALD and MASLD via gut-liver axis, typical characteristics of gut microbiota can be used as a potential diagnostic marker in ALD and MASLD. Machine learning (ML) algorithms improve diagnostic performance in various diseases. Using gut microbiota-based ML algorithms, we evaluated the diagnostic index for ALD and MASLD. Fecal 16S rRNA sequencing data of 263 ALD (control, elevated liver enzyme [ELE], cirrhosis, and hepatocellular carcinoma [HCC]) and 201 MASLD (control and ELE) subjects were collected. For external validation, 126 ALD and 84 MASLD subjects were recruited. Four supervised ML algorithms (support vector machine, random forest, multilevel perceptron, and convolutional neural network) were used for classification with 20, 40, 60, and 80 features, in which three nonsupervised ML algorithms (independent component analysis, principal component analysis, linear discriminant analysis, and random projection) were used for feature reduction. A total of 52 combinations of ML algorithms for each pair of subgroups were performed with 60 hyperparameter variations and Stratified ShuffleSplit tenfold cross validation. The ML models of the convolutional neural network combined with principal component analysis achieved areas under the receiver operating characteristic curve (AUCs) > 0.90. In ALD, the diagnostic AUC values of the ML strategy (vs. control) were 0.94, 0.97, and 0.96 for ELE, cirrhosis, and liver cancer, respectively. The AUC value (vs. control) for MASLD (ELE) was 0.93. In the external validation, the AUC values of ALD and MASLD (vs control) were > 0.90 and 0.88, respectively. The gut microbiota-based ML strategy can be used for the diagnosis of ALD and MASLD.ClinicalTrials.gov NCT04339725.

Liver stiffness measurement by magnetic resonance elastography predicts cirrhosis and decompensation in alcohol-related liver disease.

PURPOSE: To evaluate magnetic resonance elastography (MRE)-based liver stiffness measurement as a biomarker to predict the onset of cirrhosis in early-stage alcohol-related liver disease (ALD) patients, and the transition from compensated to decompensated cirrhosis in ALD. METHODS: Patients with ALD and at least one MRE examination between 2007 and 2020 were included in this study. Patient demographics, liver chemistries, MELD score (within 30 days of the first MRE), and alcohol abstinence history were collected from the electronic medical records. Liver stiffness and fat fraction were measured. Disease progression was assessed in the records by noting cirrhosis onset in early-stage ALD patients and decompensation in those initially presenting with compensated cirrhosis. Nomograms and cut-off values of liver stiffness, derived from Cox proportional hazards models were created to predict the likelihood of advancing to cirrhosis or decompensation. RESULTS: A total of 182 patients (132 men, median age 57 years) were included in this study. Among 110 patients with early-stage ALD, 23 (20.9%) developed cirrhosis after a median follow-up of 6.2 years. Among 72 patients with compensated cirrhosis, 33 (45.8%) developed decompensation after a median follow-up of 4.2 years. MRE-based liver stiffness, whether considered independently or adjusted for age, alcohol abstinence, fat fraction, and sex, was a significant and independent predictor for both future cirrhosis (Hazard ratio [HR] = 2.0-2.2, p = 0.002-0.003) and hepatic decompensation (HR = 1.2-1.3, p = 0.0001-0.006). Simplified Cox models, thresholds, and corresponding nomograms were devised for practical use, excluding non-significant or biased variables. CONCLUSIONS: MRE-based liver stiffness assessment is a useful predictor for the development of cirrhosis or decompensation in patients with ALD.

Dietary fiber alleviates alcoholic liver injury via Bacteroides acidifaciens and subsequent ammonia detoxification.

The gut microbiota and diet-induced changes in microbiome composition have been linked to various liver diseases, although the specific microbes and mechanisms remain understudied. Alcohol-related liver disease (ALD) is one such disease with limited therapeutic options due to its complex pathogenesis. We demonstrate that a diet rich in soluble dietary fiber increases the abundance of Bacteroides acidifaciens (B. acidifaciens) and alleviates alcohol-induced liver injury in mice. B. acidifaciens treatment alone ameliorates liver injury through a bile salt hydrolase that generates unconjugated bile acids to activate intestinal farnesoid X receptor (FXR) and its downstream target, fibroblast growth factor-15 (FGF15). FGF15 promotes hepatocyte expression of ornithine aminotransferase (OAT), which facilitates the metabolism of accumulated ornithine in the liver into glutamate, thereby providing sufficient glutamate for ammonia detoxification via the glutamine synthesis pathway. Collectively, these findings uncover a potential therapeutic strategy for ALD involving dietary fiber supplementation and B. acidifaciens.