RESUMO
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.
Assuntos
Bacteroides , Fígado , Animais , Camundongos , Fígado/microbiologia , Fígado/metabolismo , Fibras na Dieta/metabolismo , Humanos , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/metabolismo , Microbioma GastrointestinalRESUMO
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.
Assuntos
Microbioma Gastrointestinal , Aprendizado de Máquina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Algoritmos , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/metabolismo , RNA Ribossômico 16S/genética , Idoso , Curva ROC , Fezes/microbiologia , Fígado Gorduroso/microbiologia , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/metabolismoRESUMO
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.
Assuntos
Ácidos e Sais Biliares , Disbiose , Microbioma Gastrointestinal , Metabolismo dos Lipídeos , Hepatopatias Alcoólicas , Animais , Humanos , Masculino , Camundongos , Ácidos e Sais Biliares/metabolismo , Modelos Animais de Doenças , Disbiose/metabolismo , Disbiose/microbiologia , Disbiose/induzido quimicamente , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/etiologia , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
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.
Assuntos
Temperatura Alta , Levilactobacillus brevis , Hepatopatias Alcoólicas , Proteômica , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Animais , Levilactobacillus brevis/metabolismo , Masculino , Probióticos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , HumanosRESUMO
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.
Assuntos
Amônia , Bacteroides , Fibras na Dieta , Fatores de Crescimento de Fibroblastos , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Animais , Bacteroides/metabolismo , Camundongos , Fibras na Dieta/metabolismo , Amônia/metabolismo , Microbioma Gastrointestinal/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Fígado/metabolismo , Hepatócitos/metabolismo , Ácidos e Sais Biliares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Humanos , Inativação Metabólica , AmidoidrolasesRESUMO
Alcohol-associated liver disease (ALD) manifests as a consequence of prolonged and excessive alcohol consumption. This disease is closely associated with the interplay between gut health and liver function, which can lead to complex pathophysiological changes in the body. This review offers a comprehensive exploration of ALD's multifaceted nature, with a keen focus on its pathogenesis and the potential of nutritional and microbiota-based therapies. Insights derived from diverse case studies are utilized to shed light on how interventions can rebalance the gut microbiome and enhance liver function in ALD patients. Furthermore, the feasibility of liver transplantation and stem cell therapy as ultimate measures for ALD has been discussed, with acknowledgment of the inherent risks and challenges accompanying them. ALD's complexity underscores the necessity for a thorough understanding of its etiology and progression to devise effective treatments that mitigate its profound impact on an individual's health.
Assuntos
Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Humanos , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/terapia , Animais , Transplante de FígadoRESUMO
Probiotics can regulate gut microbiota and protect against acute alcohol-induced liver injury through the gut-liver axis. However, efficacy is strain-dependent, and their mechanism remains unclear. This study investigated the effect of lactic acid bacteria (LAB), including Lacticaseibacillus paracasei E10 (E10), Lactiplantibacillus plantarum M (M), Lacticaseibacillus rhamnosus LGG (LGG), Lacticaseibacillus paracasei JN-1 (JN-1), and Lacticaseibacillus paracasei JN-8 (JN-8), on the prevention of acute alcoholic liver injury in mice. We found that LAB pretreatment reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) and reduced hepatic total cholesterol (TC) and triglyceride (TG). JN-8 pretreatment exhibited superior efficacy in improving hepatic antioxidation. LGG and JN-8 pretreatment significantly attenuated hepatic and colonic inflammation by decreasing the expression of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) and increasing the expression of interleukin 10 (IL-10). JN-1 and JN-8 pretreatments have better preventive effects than other LAB pretreatment on intestinal barrier dysfunction. In addition, the LAB pretreatment improved gut microbial dysbiosis and bile acid (BA) metabolic abnormality. All of the strains were confirmed to have bile salt deconjugation capacities in vitro, where M and JN-8 displayed higher activities. This study provides new insights into the prevention and mechanism of LAB strains in preventing acute alcoholic liver injury.
Assuntos
Ácidos e Sais Biliares , Microbioma Gastrointestinal , Lactobacillales , Fígado , Camundongos Endogâmicos C57BL , Probióticos , Animais , Camundongos , Probióticos/administração & dosagem , Fígado/metabolismo , Masculino , Humanos , Ácidos e Sais Biliares/metabolismo , Lactobacillales/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Aspartato Aminotransferases/metabolismo , Aspartato Aminotransferases/sangue , Alanina Transaminase/metabolismo , Alanina Transaminase/sangue , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Interleucina-6/metabolismo , Interleucina-6/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Etanol/efeitos adversosRESUMO
Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.
Assuntos
Cumarínicos , Estresse do Retículo Endoplasmático , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Fígado , Camundongos Endogâmicos C57BL , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Disbiose/microbiologia , Humanos , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificaçãoRESUMO
BACKGROUND: Alcoholic liver disease (ALD) and metabolic-dysfunction associated steatotic liver disease (MASLD) are common, and gut microbiota (GM) is involved with both. Here we compared GM composition in animal models of MASLD and ALD to assess whether there are specific patterns for each disease. METHODS: MASLD model- adult male Sprague Dawley rats, randomized into two groups: MASLD-control (n=10) fed a standard diet; MASLD-group (n=10) fed a high-fat-choline-deficient diet for 16 weeks. ALD model- adult male Wistar rats randomized: ALD-control (n=8) fed a standard diet and water+0.05% saccharin, ALD groups fed with sunflower seed and 10% ethanol+0.05% saccharin for 4 or 8 weeks (ALC4, n=8; ALC8, n=8). ALC4/8 on the last day received alcoholic binge (5g/kg of ethanol). Afterwards, animals were euthanized, and feces were collected for GM analysis. RESULTS: Both experimental models induced typical histopathological features of the diseases. Alpha diversity was lower in MASLD compared with ALD (p<0.001), and structural pattern was different between them (P<0.001). Bacteroidetes (55.7%), Firmicutes (40.6%), and Proteobacteria (1.4%) were the most prevalent phyla in all samples, although differentially abundant among groups. ALC8 had a greater abundance of the phyla Cyanobacteria (5.3%) and Verrucomicrobiota (3.2%) in relation to the others. Differential abundance analysis identified Lactobacillaceae_unclassified, Lachnospiraceae_NK4A136_group, and Turicibacter associated with ALC4 and the Clostridia_UCG_014_ge and Gastranaerophilales_ge genera to ALC8. CONCLUSION: In this study, we demonstrated that the structural pattern of the GM differs significantly between MASLD and ALD models. Studies are needed to characterize the microbiota and metabolome in both clinical conditions to find new therapeutic strategies. BACKGROUND: â¢Changes in the composition of the intestinal microbiota are related to the development of alcoholic liver disease and metabolic-dysfunction associated steatotic liver disease. BACKGROUND: â¢The diversity of the intestinal microbiota was lower in animals with MASLD compared to ALD. BACKGROUND: â¢The structural pattern of the intestinal microbiota was significantly different among the experimental groups. BACKGROUND: â¢Studies are needed to characterize the composition of the intestinal microbiota and metabolome to find new therapeutic strategies.
Assuntos
Fígado Gorduroso , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Ratos , Animais , Masculino , Sacarina , Ratos Sprague-Dawley , Modelos Animais de Doenças , Ratos Wistar , Hepatopatias Alcoólicas/microbiologia , EtanolRESUMO
BACKGROUND & AIMS: Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic + binge ethanol feeding. METHODS: After injection of adeno-associated virus-green fluorescent protein or AAV-FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge. RESULTS: Chronic + binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by Il6, Tgfß, and Tnfα, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including Enterococcus faecalis, Escherichia coli, and Clostridium perfringens. CONCLUSIONS: Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.
Assuntos
Ácidos e Sais Biliares , Modelos Animais de Doenças , Disbiose , Etanol , Fatores de Crescimento de Fibroblastos , Hepatopatias Alcoólicas , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Ácidos e Sais Biliares/metabolismo , Disbiose/microbiologia , Disbiose/patologia , Disbiose/induzido quimicamente , Camundongos , Feminino , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/etiologia , Etanol/efeitos adversos , Etanol/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Fígado/patologia , Consumo Excessivo de Bebidas Alcoólicas/complicações , Consumo Excessivo de Bebidas Alcoólicas/patologia , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , HumanosRESUMO
BACKGROUND: Alcoholic liver disease (ALD) is a chronic liver injury caused by excessive alcohol consumption, could be impacted by gut-liver axis dysfunction. The gut microbiota plays a crucial role in the development and progression of ALD. Given the role of gut-liver axis dysfunction in ALD, strategies targeting gut microbiota modulation have gained interest for therapeutic interventions. Bifidobacterium longum subsp. longum BL21 has shown promise in alleviating gut microbiota disturbances and metabolic regulation in high-fat diet-induced obesity and type 2 diabetes mellitus models. Thus, this study aimed to evaluate the therapeutic effect of BL21 on ALD mice and explore the potential mechanism by which the gut microbiota mediates the amelioration of ALD by BL21. METHODS: A total of 30 mice were randomly assigned to three groups (n = 10 mice/group): a healthy control (CTL) group, an ALD group, and a BL21 group. Each group was fed a Lieber-DeCarli liquid diet with (ALD and BL21) or without alcohol (CTL). The intervention period lasted 6 weeks, after which the effects of BL21 intervention (intragastric administration of 1 billion CFU of BL21 daily) on serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, hepatic oxidative stress, serum inflammatory cytokine levels, and gut microbiota composition in ALD mice were investigated. RESULTS: Dietary BL21 reduced the ethanol-induced abnormal elevation of serum AST and ALT levels in ALD mice (P < 0.001 for both). BL21 treatment significantly attenuated alcohol-induced hepatic oxidative stress by decreasing malondialdehyde concentration and increasing superoxide dismutase, catalase, and glutathione concentrations in the livers of ALD mice. In addition, the serum levels of tumor necrosis factor-alpha, interleukin-1 beta (IL-1ß), and IL-6 were significantly lower (P < 0.001 for both), while that of IL-10 was significantly higher (P < 0.05), in the BL21 group than in the ALD group. Intestinal microbiota analysis showed an increased relative abundance of Escherichia/Shigella, Enterococcus, and Alistipes in the ALD group compared with the CTL group. BL21 intervention increased the relative abundance of Bifidobacterium and Akkermansia compared with the ALD group. CONCLUSION: Dietary BL21 ameliorates ALD via enhancement of the hepatic antioxidant capacity and modulation of the gut microbiota and may therefore be a promising strategy to prevent or treat ALD.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Camundongos , Animais , Antioxidantes/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Fígado , Bifidobacterium , Etanol/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Ganoderma lucidum spore powder (GLSP) has abundant pharmacological activities. However, the difference in the hepatoprotective function of sporoderm-broken and sporoderm-unbroken Ganoderma spore powder has not been studied. This study is the first to investigate the effects of both sporoderm-damaged and sporoderm-intact GLSP on the improvement of acute alcoholic liver injury in mice and gut microbiota of mice. METHODS: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and interleukin 1ß (IL-1ß), interleukin 18 (IL-18), and tumor necrosis factor-α (TNF-α) levels in liver tissues from mice in each group were detected by enzyme-linked immunosorbent assay (ELISA) kits, and histological analysis of liver tissue sections was performed to evaluate the liver-protecting effects of both sporoderm-broken and sporoderm-unbroken GLSP. Additionally, 16S rDNA sequencing of feces from the bowels of mice was performed to compare the regulatory effects of both sporoderm-broken and sporoderm-unbroken GLSP on the gut microbiota of mice. RESULTS: Compared with those in the 50% ethanol model group (MG), sporoderm-broken GLSP significantly reduced serum AST and ALT levels (p < 0.0001) and the release of the inflammatory factors, including IL-1ß, IL-18, and TNF-α (p < 0.0001), and effectively improved the pathological state of liver cells; sporoderm-unbroken GLSP significantly reduced the ALT content (p = 0.0002) and the release of the inflammatory factors, including IL-1ß (p < 0.0001), IL-18 (p = 0.0018), and TNF-α (p = 0.0005), and reduced the serum AST content, but the reduction was not significant; compared with the gut microbiota of the MG, sporoderm-broken GLSP reduced the levels of Verrucomicrobia and Escherichia_Shigella, increased the relative abundance of beneficial bacteria such as Bacteroidetes, and decreased the abundance levels of harmful bacteria, such as Proteobacteria and Candidatus_Saccharibacteria; sporoderm-unbroken GLSP could reduce the abundance levels of harmful bacteria, such as Verrucomicrobia and Candidatus_Saccharibacteria; and GLSP treatment alleviates the downregulation of the levels of translation, ribosome structure and biogenesis, and lipid transport and metabolism in liver-injured mice; Conclusions: GLSP can alleviate the imbalance of gut microbiota and improve liver injury, and the effect of sporoderm-broken GLSP is better.
Assuntos
Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Reishi , Animais , Camundongos , Interleucina-18 , Fígado , Pós , Esporos Fúngicos , Fator de Necrose Tumoral alfa , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/terapiaRESUMO
Microbiome alterations are emerging as one of the most important factors that influence the course of alcohol use disorder (AUD). Recent advances in bioinformatics enable more robust and accurate characterization of changes in the composition of the microbiome. In this study, our objective was to provide the most comprehensive and up-to-date evaluation of microbiome alterations associated with AUD and alcoholic liver disease (ALD). To achieve it, we have applied consistent, state of art bioinformatic workflow to raw reads from multiple 16S rRNA sequencing datasets. The study population consisted of 122 patients with AUD, 75 with ALD, 54 with non-alcoholic liver diseases, and 260 healthy controls. We have found several microbiome alterations that were consistent across multiple datasets. The most consistent changes included a significantly lower abundance of multiple butyrate-producing families, including Ruminococcaceae, Lachnospiraceae, and Oscillospiraceae in AUD compared to HC and further reduction of these families in ALD compared with AUD. Other important results include an increase in endotoxin-producing Proteobacteria in AUD, with the ALD group having the largest increase. All of these alterations can potentially contribute to increased intestinal permeability and inflammation associated with AUD and ALD.
Assuntos
Alcoolismo , Microbioma Gastrointestinal , Lactobacillales , Hepatopatias Alcoólicas , Microbiota , Humanos , Alcoolismo/genética , Alcoolismo/microbiologia , RNA Ribossômico 16S/genética , Microbioma Gastrointestinal/genética , Hepatopatias Alcoólicas/microbiologia , Lactobacillales/genética , Fígado/microbiologiaRESUMO
Chronic alcohol consumption is associated with intestinal fungal dysbiosis, yet we understand little about how alterations of intestinal fungi (mycobiota) contribute to the pathogenesis of alcohol-associated liver disease. By reanalyzing internal transcribed spacer 2 amplicon sequencing of fecal samples from a cohort of 66 patients with alcohol use disorder for presence (as opposed to relative abundance) of fungal species, we observed that the presence of Malassezia restricta was associated with increased markers of liver injury. M. restricta exacerbates ethanol-induced liver injury both in acute binge and chronic ethanol-feeding models in mice. Using bone marrow chimeric mice, we found that the disease exacerbating effect by M. restricta was mediated by C-type lectin domain family 4, member N on bone marrow-derived cells. M. restricta induces inflammatory cytokines and chemokines in Kupffer cells through C-type lectin domain family 4, member N signaling. Targeting fungal pathobionts might be a therapeutic strategy for alcohol-associated liver disease.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Hepatopatias Alcoólicas , Animais , Camundongos , Etanol/efeitos adversos , Hepatopatias Alcoólicas/microbiologia , Lectinas Tipo C/genéticaRESUMO
OBJECTIVES: Alcoholic liver disease (ALD) is the leading cause of alcohol-related deaths worldwide. Experimental ALD models are expensive and difficult to reproduce. A low-cost, reproducible ALD model was developed, and liver damage compared with the gut microbiota. The aims of this study were to develop an experimental model of ALD, through a high-fat diet, the chronic use of ethanol, and intragastric alcohol binge; and to evaluate the composition of the gut microbiota and its correlation with markers of inflammatory and liver disease progression in this model. METHODS: Adult male Wistar rats were randomized (N = 24) to one of three groups: control (standard diet and water + 0.05% saccharin), ALC4 and ALC8 (sunflower seed, 10% ethanol + 0.05% saccharin for 4 and 8 wk, respectively). On the last day, ALC4/8 received alcoholic binge (5 g/kg). Clinical, nutritional, biochemical, inflammatory, pathologic, and gut microbiota data were analyzed. RESULTS: ALC4/8 animals consumed more alcohol and lipids (P < 0.01) and less total energy, liquids, solids, carbohydrates, and proteins (P < 0.01), and gained less weight (P < 0.01) than controls. ALC8 had lower Lee index scores than controls and ALC4 (P < 0.01). Aminotransferases increased and albumin diminished in ALC4/8 but not in the control group (P < 0.03 for all). Glucose and aspartate transaminase/alanine aminotransaminase ratios were higher in the ALC8 rats than in the controls (P < 0.03). Cholesterol was higher in ALC4 and lower in ALC8 compared with controls (P < 0.03). Albumin and high-density lipoprotein cholesterol levels were lower in ALC8 (P < 0.03). Hepatic concentration of triacylglycerols was higher in ALC8 than in ALC4 and controls (P < 0.05). ALC4/8 presented microvesicular grade 2 and 3 steatosis, respectively, and macrovesicular grade 1. No change in the gene expression of inflammatory markers between groups was seen. ALC4/8 had lower fecal bacterial α-diversity and relative abundance of Firmicutes (P < 0.005) and greater Bacterioidetes (P < 0.0007) and Protobacteria (P < 0.001) than controls. Gut microbiota correlated with serum and liver lipids, steatosis, albumin, and aminotransferases (P < 0.01 for all). CONCLUSION: The model induced nutritional, biochemical, histologic, and gut microbiota changes, and appears to be useful in the study of therapeutic targets.
Assuntos
Fígado Gorduroso , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Ratos , Masculino , Animais , Microbioma Gastrointestinal/genética , Sacarina/metabolismo , Ratos Wistar , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Fígado/metabolismo , Etanol/metabolismo , Fígado Gorduroso/metabolismo , Transaminases/metabolismo , LipídeosRESUMO
Liver diseases are responsible for over 2 million deaths each year and the number is rapidly increasing. There is a strong link between edibles, gut microbiota, liver fat and the liver damage. There are very limited therapeutic options for treatment specifically for Alcoholic liver disease (ALD) and Non-Alcoholic liver disease (NAFLD). Recently, identified Edible Exosomes-like nanoparticles (ELNs) are plant derived membrane bound particles, released by microvesicular bodies for cellular communication and regulate immune responses against many pathogens. Many studies have identified their role as hepatoprotective agent as they carry bioactive material as cargoes which are transferred to recipient cells and affect various biological functions in liver. They are also known to carry specific miRNA, which increases the copy number of beneficial bacteria and the production of lactic acid metabolites in gut and hence restrains from liver injury through portal vein. Few in-vitro studies also have been reported about the anti-inflammatory, anti-oxidant and detoxification properties of ELNs which again protects the liver. The properties such as small size, biocompatibility, stability, low toxicity and non-immunogenicity make ELNs as a better therapeutic option. But, till now, studies on the effect of ELNs as therapeutics are still at its infancy yet promising. Here we discuss about the isolation, characterization, their role in maintaining the gut microbiome and liver homeostasis. Also, we give an outline about the latest advances in ELNs modifications, its biological effects, limitations and we propose the future prospective of ELNs as therapeutics.
Assuntos
Exossomos , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Nanopartículas , Humanos , Hepatopatias Alcoólicas/microbiologiaRESUMO
A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.
Assuntos
Transtorno da Compulsão Alimentar/metabolismo , Transtorno da Compulsão Alimentar/patologia , Progressão da Doença , Inflamassomos/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Receptores de Superfície Celular/metabolismo , Consumo de Bebidas Alcoólicas , Animais , Transtorno da Compulsão Alimentar/microbiologia , Ceco/microbiologia , Doença Crônica , Modelos Animais de Doenças , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Microbioma Gastrointestinal , Mucosa Intestinal/patologia , Fígado/lesões , Fígado/patologia , Hepatopatias Alcoólicas/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Receptores de Superfície Celular/deficiência , Transdução de SinaisRESUMO
Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wild-type mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD.
Assuntos
Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo , Metaboloma , Microbiota , Transcriptoma , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Fezes/microbiologia , Feminino , Hepatócitos/metabolismo , Hepatopatias Alcoólicas/microbiologia , MAP Quinase Quinase Quinase 1/antagonistas & inibidores , Masculino , Camundongos Endogâmicos C57BL , Regulação para CimaRESUMO
Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.