The gastrointestinal tract is the natural habitat for a huge community of microorganisms, comprising bacteria, viruses, fungi and yeast. This microbial ecosystem codevelops with the host throughout ...life and is subject to a complex interplay that depends on multiple factors including host genetics, nutrition, life-style, stress, diseases and antibiotics use. The gut microbiota, that refers to intestinal bacteria, has profound influence on the host immune system, metabolism and nervous system. Indeed, intestinal bacteria supply the host with essential nutrients such as vitamins, metabolize bile acids and undigested compounds, defend against pathogen invasion, participate to the development of the intestinal architecture and the intestinal immune system and play an important role in the maintenance of the gut barrier function. More recently, the gut microbiota has been shown to influence brain functions, such as myelin synthesis, the blood-brain barrier permeability and neuroinflammatory responses but also mood and behavior. The cross-talk between microbes and the host implicates a vast array of signaling pathways that involve many different classes of molecules like metabolites produced by the bacteria from dietary or endogenous sources of carbohydrates and proteins (i.e. short-chain fatty acids (SCFAs), indole), neurotransmitters and inflammatory cytokines. This review will focus on the involvement of the gut microbiota in the pathophysiological aspects of alcohol dependence related to the gut barrier function, liver damage and psychological disturbances. We will also discuss the possibility to create new and realistic humanized animal models of alcohol dependence by the use of fecal transplantation.
•The gut microbiota is a dynamic ecosystem that influences host heath, including brain functions and behavior.•Alcohol abuse has a detrimental effect on the gut barrier and on intestinal microbiota.•Fecal transplantation is a new tool to analyze the causal role of gut microbiota in brain diseases.•Probiotics and prebiotics might represent a promising therapeutic approach in alcohol-use disorder.
Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol‐related liver ...disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal‐specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti–Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90‐day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11‐8.82; P = 0.031). Conclusion: Patients with alcohol‐associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.
Sarcopenia was initially defined as loss of muscle mass, strength and function related to aging. This phenomenon is a multifactorial process. The evaluation of the geriatric population in which ...sarcopenia has extensively been studied opens the field for other chronic diseases. Cirrhosis is one of them and the term “sarcopenia” is now also used in this pathological situation. It must be emphasized that the pathophysiology of sarcopenia in cirrhosis is likely different from the pathogenesis in geriatric patients. Furthermore, cirrhosis has heterogeneous causes. Therefore, we need a better understanding of the changes in muscle physiology specifically in chronic liver diseases as well as easy, accurate, reproducible and validated tools, taking into consideration etiology specific aspects to identify sarcopenia in every cirrhotic patient.
The prevalence of alcohol use disorder (AUD) and metabolic dysfunction-associated fatty liver disease (MAFLD) are increasing worldwide, leading to the increasing likelihood of both etiologies ...contributing to a patient's liver disease. However, the effects of modest alcohol use in NAFLD are controversial and more studies are needed. We compared the intestinal viromes of patients with AUD and NAFLD in order to evaluate the effect of alcohol consumption on the intestinal viromes of NAFLD patients by extracting virus-like particles and performing metagenomic sequencing.
Viral nucleic acids were extracted from fecal samples and subjected to metagenomic sequencing. We demonstrate significant differences in the intestinal viromes of NAFLD and AUD patients, and that alcohol use in NAFLD patients reclassified to MAFLD accounted for significant differences in the intestinal viromes. The relative abundance of several Lactococcus phages was more similar between AUD patients and alcohol-consuming MAFLD patients than non-alcohol-consuming MAFLD patients and control subjects, and multivariate modeling using the most discriminating Lactococcus phages could better predict alcohol use in the MAFLD population than the alcohol-associated liver disease/NAFLD Index. Significant differences in the viral composition and diversity were also seen between MAFLD patients with low and moderate alcohol consumption compared with no alcohol consumption.
The intestinal virome of MAFLD patients who consume low to moderate amounts of alcohol are significantly different from those who do not, and many features of the intestinal virome of alcohol-consuming MAFLD patients resemble that of AUD patients.
The translocation of bacteria and bacterial products into the circulation contributes to alcoholic liver disease. Intestinal bacterial overgrowth is common in patients with alcoholic liver disease. ...The aims of our study were to investigate bacterial translocation, changes in the enteric microbiome, and its regulation by mucosal antimicrobial proteins in alcoholic liver disease. We used a mouse model of continuous intragastric feeding of alcohol or an isocaloric diet. Bacterial translocation occurred prior to changes observed in the microbiome. Quantitative changes in the intestinal microflora of these animals were assessed first using conventional culture techniques in the small and large intestine. Although we found no difference after 1 day or 1 week, intestinal bacterial overgrowth was observed in the gastrointestinal tract of mice fed alcohol for 3 weeks compared with control mice fed an isocaloric liquid diet. Because <20% of all gastrointestinal bacteria can be cultured using conventional methodologies, we performed massively parallel pyrosequencing to further assess the qualitative changes in the intestinal microbiome following alcohol exposure. Sequencing of 16S ribosomal RNA genes revealed a relative abundance of Bacteroidetes and Verrucomicrobia bacteria in mice fed alcohol compared with a relative predominance of Firmicutes bacteria in control mice. With respect to the host's transcriptome, alcohol feeding was associated with down‐regulation in gene and protein expression of bactericidal c‐type lectins Reg3b and Reg3g in the small intestine. Treatment with prebiotics partially restored Reg3g protein levels, reduced bacterial overgrowth, and lessened alcoholic steatohepatitis. Conclusion: Alcohol feeding is associated with intestinal bacterial overgrowth and enteric dysbiosis. Intestinal antimicrobial molecules are dysregulated following chronic alcohol feeding contributing to changes in the enteric microbiome and to alcoholic steatohepatitis. (HEPATOLOGY 2011)
Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but ...convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of β-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations.
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•Gut alterations are related to impaired sociability in alcohol use disorder patients•Human-to-mice microbiota transplantation reproduces metabolic and behavioral disorders•Microbial ethanol production is linked to reduced β-hydroxybutyrate (BHB) synthesis•In mice and humans, BHB level is associated with depression and social impairments
Accumulating evidence highlights the importance of the gut-brain axis in alcohol use disorders. In this translational study, Leclercq et al. show that the transplantation of gut microbiota from alcoholic patients to mice induces metabolic disturbances impacting the adipose tissue and the liver, resulting in reduced β-hydroxybutyrate synthesis that drives neurobiological and behavioral alterations.
There is a demand for serum markers for the routine assessment of the progression of liver cancer. We previously found that serum N-linked sugar chains are altered in hepatocellular carcinoma (HCC). ...Here, we studied glycomic alterations during development of HCC in a rat model.
Rat HCC was induced by the hepatocarcinogen, diethylnitrosamine (DENA). N-glycans were profiled using the DSA-FACE technique developed in our laboratory.In comparison with control rats, DENA rats showed a gradual but significant increase in two glycans (R5a and R5b) in serum total N-glycans during progression of liver cirrhosis and cancer, and a decrease in a biantennary glycan (P5). The log of the ratio of R5a to P1 (NGA2F) and R5b to P1 log(R5a/P1) and log(R5b/P1) were significantly (p < 0.0001) elevated in HCC rats, but not in rats with cirrhosis or fibrosis or in control rats. We thus propose a GlycoTest model using the above-mentioned serum glycan markers to monitor the progression of cirrhosis and HCC in the DENA-treated rat model. When DENA-treated rats were subsequently treated with farnesylthiosalicyclic acid, an anticancer drug, progression to HCC was prevented and GlycoTest markers (P5, R5a and R5b) reverted towards non-DENA levels, and the HCC-specific markers, log(R5a/P1) and log(R5b/P1), normalized completely.
We found an increase in core-alpha-1,6-fucosylated glycoproteins in serum and liver of rats with HCC, which demonstrates that fucosylation is altered during progression of HCC. Our GlycoTest model can be used to monitor progression of HCC and to follow up treatment of liver tumors in the DENA rat. This GlycoTest model is particularly important because a rapid non-invasive diagnostic procedure for tumour progression in this rat model would greatly facilitate the search for anticancer drugs.
BACKGROUND/GOALS:To date, there is no consensus on optimal cut-off values and timing of transient elastography (TE, Fibroscan) for fibrosis staging and prediction of portal hypertension in alcoholic ...liver disease. We evaluated the accuracy of Fibroscan for the diagnosis of fibrosis and clinically significant portal hypertension in alcoholic patients.
STUDY:Heavy drinkers admitted to our standardized alcohol withdrawal program were evaluated by Fibroscan, by transjugular hepatic venous pressure gradient (HVPG) measurement and liver biopsy if significant fibrosis was suspected and by upper gastrointestinal endoscopy. All investigations were performed within 3 days of admission. Patients who had remained abstinent for 2 weeks underwent a second Fibroscan.
RESULTS:A total of 118 patients were included. Fibroscan correlated well with histology and HVPG. Negative predictive value of 92% and 93% for ruling out severe fibrosis (≥F3) and cirrhosis, and optimal cut-offs at ≥11.7, ≥15.2, and ≥21.2 kPa for F2, F3, and F4, respectively, were found. In abstinent patients, a mean decrease of 2.7 kPa improved concordance between Fibroscan and histology. A TE value of 30.6 kPa predicted a HVPG>10 mm Hg with 94% specificity and showed a good negative predictive value of 84% for ruling out the presence of varices at endoscopy. Steatosis, alcoholic hepatitis, sinusoidal fibrosis, cholestasis, and high transaminases did not influence TE values.
CONCLUSIONS:Fibroscan is an accurate non-invasive method for the diagnosis of fibrosis in alcoholic patients. TE values below 11 and 30 kPa likely rule out significant fibrosis and varices, respectively.
Extracellular vesicles (EVs) released during cell stress, or demise, can contain a barcode of the cell origin, including specific microRNAs (miRNAs). Here, we tested the hypothesis that during early ...alcoholic steatohepatitis (ASH) development, hepatocytes (HCs) release EVs with an miRNA signature that can be measured in circulation. A time‐course experiment showed that after 2 weeks of intragastric infusion, a time point that results in isolated steatosis, there was no increase of blood EVs. After 4 weeks of infusion, mice developed features of early ASH accompanied by a marked increase in the level of EVs in blood (P < 0.05), as well as in culture media of isolated HCs (P < 0.001) and hepatic macrophages (P < 0.001), with HCs being the predominant source of EVs. The transcriptome analysis of HC‐EVs from ASH mice detected differentially expressed miRNAs, including nine significantly up‐regulated and four significantly down‐regulated miRNAs. Target prediction and pathway analyses of the up‐regulated miRNAs identified 121 potential target genes involved in inflammatory and cancer pathways, such as nuclear factor kappa B, EGF, Wnt, and B‐cell lymphoma 2. Three miRNAs, let7f, miR‐29a, and miR‐340, were increased in blood EVs from ASH mice (P < 0.05), but not in blood EVs from three other models of chronic liver injury, including bile duct ligation, nonalcoholic steatohepatitis, and obese mice, as well as EVs released from hepatocytes exposed to ethanol. Blood EV level (P < 0.01) and three miRNAs (P < 0.05) were significantly increased in patients with ambulatory mild ALD as compared to nonalcoholics. Conclusion: Damaged hepatocytes from ASH mice are a key EV source with a specific miRNA cargo, which are specific for ASH‐related liver injury. These findings uncover EVs as a potentially novel diagnostic for ASH. (Hepatology 2017;65:475‐490).
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•Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis.•Total and conjugated bile acids correlated positively with FGF19 and with disease ...severity (MELD score).•Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis.
The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis.
Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis.
We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis.
Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans.
Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis.
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