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BACKGROUND AND AIMS: The prevalence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) is higher in patients with cirrhosis, compared to control patients without liver disease. The exact mechanism for this is unknown but could include liver inflammation. In this study we investigate whether cirrhosis is the primum movens of IR or if impaired insulin sensitivity is already present in non-cirrhotic patients with chronic liver diseases. METHODS: Patients were recruited and divided into three groups: control (CTL), chronic liver disease without cirrhosis (CLD) and cirrhosis (CIR). In patients not taking pharmacological treatment for T2DM, IR was quantified using the homeostasis model assessment of insulin resistance (HOMA-IR). The proportion of patients with T2DM as well as HOMA-IR levels among different disease etiologies were recorded and compared. RESULTS: 532 patients were included in our study. Median glycemia and insulinemia and therefore HOMA-IR values were significantly different between the three cohorts (p-value <0.001): IR levels in CLD subjects lie between those seen in CTL and CIR subjects. The proportion of diabetic patients in the two case categories also differs (p-value = 0.027): one quarter of CLD subjects and one third of CIR patients suffer from T2DM. Finally, HOMA-IR levels vary according to disease etiology (p-value <0.001): metabolic steatosis and chronic viral hepatitis C are at greater risk than alcohol and other disease causes. CONCLUSION: CLD is already a predisposing factor to T2DM, regardless of the presence of CIR. CIR is a factor which elicits additional increase in insulin levels. Metabolic steatosis and hepatitis C are associated with more severe IR.
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OBJECTIVE: Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. DESIGN: In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). RESULT: Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. CONCLUSIONS: We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.
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BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.
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Hepatitis Alcohólica , Receptores de Hidrocarburo de Aril , Humanos , Receptores de Hidrocarburo de Aril/sangre , Receptores de Hidrocarburo de Aril/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Hepatitis Alcohólica/mortalidad , Hepatitis Alcohólica/sangre , Adulto , Estudios de Casos y Controles , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/sangre , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Tasa de Supervivencia , Células Hep G2 , Anciano , Biomarcadores/sangreRESUMEN
The fungal microbiota plays an important role in the pathogenesis of alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to compare changes of the fecal fungal microbiota between patients with ALD and NAFLD and to elucidate patterns in different disease stages between the two conditions. We analyzed fungal internal transcribed spacer 2 (ITS2) sequencing using fecal samples from a cohort of 48 patients with ALD, 78 patients with NAFLD, and 34 controls. The fungal microbiota differed significantly between ALD and NAFLD. The genera Saccharomyces, Kluyveromyces, Scopulariopsis, and the species Candida albicans (C. albicans), Malassezia restricta (M. restricta), Scopulariopsis cordiae (S. cordiae) were significantly increased in patients with ALD, whereas the genera Kazachstania and Mucor were significantly increased in the NAFLD cohort. We identified the fungal signature consisting of Scopulariopsis, Kluyveromyces, M. restricta, and Mucor to have the highest discriminative ability to detect ALD vs NAFLD with an area under the curve (AUC) of 0.93. When stratifying the ALD and NAFLD cohorts by fibrosis severity, the fungal signature with the highest AUC of 0.92 to distinguish ALD F0-F1 vs NAFLD F0-F1 comprised Scopulariopsis, Kluyveromyces, Mucor, M. restricta, and Kazachstania. For more advanced fibrosis stages (F2-F4), the fungal signature composed of Scopulariopsis, Kluyveromyces, Mucor, and M. restricta achieved the highest AUC of 0.99 to differentiate ALD from NAFLD. This is the first study to identify a fungal signature to differentiate two metabolic fatty liver diseases from each other, specifically ALD from NAFLD. This might have clinical utility in unclear cases and might hence help shape treatment approaches. However, larger studies are required to validate this fungal signature in other populations of ALD and NAFLD.
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Microbioma Gastrointestinal , Hepatopatías Alcohólicas , Micobioma , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/patología , Hepatopatías Alcohólicas/patología , Fibrosis , Hígado/patología , Cirrosis Hepática/patologíaRESUMEN
Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine, but the underlying mechanisms are not fully understood. In this review, we discuss the effects of alcohol on small and large intestinal functions, such as leaky gut, dysbiosis and alterations of intestinal epithelium and gut immune dysfunctions, commonly referred to as alcohol-associated bowel disease (ABD). To date, detailed mechanistic insights into ABD are lacking. Accumulating evidence suggests a pathogenic role of ethanol metabolism in dysfunctions of the intestinal tract. Ethanol metabolism generates acetaldehyde and acetate, which could potentially promote functional disruptions of microbial and host components of the intestinal barrier along the gastrointestinal tract. The potential involvement of acetaldehyde and acetate in the pathogenesis of the underlying ABD, including cancer, is discussed. We also highlight some gaps in knowledge existing in the field of ABD. Finally, we discuss future directions in exploring the role of acetaldehyde and acetate generated during chronic alcohol intake in various pathologies affecting different sites of the intestinal tract.
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BACKGROUND AND RATIONALE: In the context of gut leakiness and translocation of microbial products in alcohol-associated liver disease (ALD), it is possible that systemic and liver inflammation involve the activation of circulating monocyte through gut-derived factors. We explored the association between monocytes, microbial translocation, systemic inflammation, and ALD. METHODS: Patients with alcohol use disorder following a rehabilitation program were compared with healthy controls. We determined the circulating number and proportion of monocyte subsets by FACS. The activation of signaling pathways by gut-derived microbes was analyzed by quantitative PCR in isolated monocytes. Cytokines secretion by monocytes and phagocytosis were assessed in vitro. Serum microbial translocation markers and cytokines were measured by ELISA and multiplex assay, respectively. ALD severity and liver inflammatory responses were analyzed in liver biopsies by various methods. RESULTS: In patients with alcohol use disorder, the number of blood monocytes increased compared with controls. Monocytes from patients with alcohol use disorder upregulated IL-1ß and IL-8 together with toll-like receptor 2 and downstream AP-1, while fungal sensor CARD9 was downregulated. IL-1ß and IL-8 were actively secreted upon stimulation in vitro with the toll-like receptor 2 ligand peptidoglycan. Exposure with Escherichia coli confirmed preserved bacterial phagocytic activity. In contrast, Candida albicans stimulation leads to downregulation of IL-1ß and TNFα compared with controls. Systemic cytokines and monocyte changes correlated with microbial translocation. Hepatic IL-1ß and IL-8 increased with ALD severity together with liver macrophage activation and upregulation of chemokines involved in monocyte attraction. CONCLUSIONS: Our results point to the contribution of activated monocytes to systemic inflammation and ALD. Monocytes likely infiltrate the liver, transform into monocyte-derived macrophages and release IL-1ß and IL-8 in response to peptidoglycan and toll-like receptor 2 activation.
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Alcoholismo , Hepatopatías Alcohólicas , Humanos , Monocitos/metabolismo , Receptor Toll-Like 2/metabolismo , Interleucina-8 , Alcoholismo/complicaciones , Peptidoglicano/metabolismo , Citocinas/metabolismo , Inflamación , Hepatopatías Alcohólicas/metabolismoRESUMEN
BACKGROUND AND AIMS: The progression of alcohol-associated liver disease (ALD) in its early precirrhotic stages can be a silent process. Serum keratin 18 levels (K18-M65) predict severe events and mortality in advanced stages of ALD, but data on this biomarker in early stages are scarce. We evaluated the diagnostic accuracy of K18-M65 levels in identifying early forms of ALD. METHODS: We prospectively evaluated two cohorts of actively drinking patients with alcohol use disorder (AUD) following a rehabilitation program (training (n = 162) and validation (n = 78)) and matched healthy controls (n = 21). Clinical, laboratory, and imaging data were used to distinguish AUD patients with simple steatosis (minimal ALD) and steatohepatitis/fibrosis (early ALD). We measured serum K18-M65 levels and assessed their ability to predict early ALD. RESULTS: High levels of K18-M65 characterized AUD patients with early ALD, while levels in the minimal ALD group were similar to those in healthy controls. K18-M65 levels distinguished minimal liver disease from early ALD (AUROC = 0.8704; p < 0.0001) with an optimal cutoff at 265.9 U/L. K18-M65 levels strongly correlated with transaminases and predicted early ALD (OR 25.81; 95% CI 3.166-336.1; p < 0.0001), controlled attenuation parameter, and liver stiffness independently from transaminases and other potential confounders. K18-M65 levels did not discriminate between fibrosis and steatohepatitis but correlated with histological signs of hepatocellular injury and inflammation (all p < 0.05). The K18-M65 cutoff detected early ALD in the validation cohort with high accuracy (sensitivity 86.67%, specificity 96.67%) and a very high positive likelihood ratio (28.6; 95% CI 4.14-197.73). CONCLUSIONS: Serum K18-M65 levels can be used as a biomarker to detect early ALD stages with excellent predictive value.
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BACKGROUND: Anxiety and depression are psychopathological states frequently co-occurring with severe alcohol use disorder (SAUD). These symptoms generally disappear with abstinence but may persist in some patients, increasing the relapse risk. METHODS: The cerebral cortex thickness of 94 male patients with SAUD was correlated with symptoms of depression and anxiety, both measured at the end (2-3 weeks) of the detoxification treatment. Cortical measures were obtained using surface-based morphometry implemented with Freesurfer. RESULTS: Depressive symptoms were associated with reduced cortical thickness in the superior temporal gyrus of the right hemisphere. Anxiety level was correlated with lower cortical thickness in the rostral middle frontal region, inferior temporal region, and supramarginal, postcentral, superior temporal, and transverse temporal regions of the left hemisphere, as well as with a large cluster in the middle temporal region of the right hemisphere. CONCLUSIONS: At the end of the detoxification stage, the intensity of depressive and anxiety symptoms is inversely associated with the cortical thickness of regions involved in emotions-related processes, and the persistence of the symptoms could be explained by these brain deficits.
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Alcoholismo , Humanos , Masculino , Alcoholismo/complicaciones , Alcoholismo/diagnóstico por imagen , Alcoholismo/patología , Corteza Cerebral/diagnóstico por imagen , Encéfalo , Ansiedad/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration in mice causes migration of Candida albicans (C. albicans)-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin decreased C. albicans-specific Th17 cells in the liver and reduced ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens developed more severe ethanol-induced liver disease than transgene-negative littermates. Adoptively transferring Candida-specific TCR transgenic T cells or polyclonal C. albicans-primed T cells exacerbated ethanol-induced liver disease in wild-type mice. Interleukin-17 (IL-17) receptor A signaling in Kupffer cells was required for the effects of polyclonal C. albicans-primed T cells. Our findings indicate that ethanol increases C. albicans-specific Th17 cells, which contribute to alcohol-associated liver disease.
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Candida albicans , Células Th17 , Ratones , Animales , Candida , Ratones Transgénicos , Etanol/toxicidadRESUMEN
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.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Hepatopatías Alcohólicas , Animales , Ratones , Etanol/efectos adversos , Hepatopatías Alcohólicas/microbiología , Lectinas Tipo C/genéticaRESUMEN
BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
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Alcoholismo , Hepatopatías Alcohólicas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Viroma , Consumo de Bebidas Alcohólicas/efectos adversos , EtanolRESUMEN
BACKGROUND & AIMS: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes. METHODS: Demographic, clinical, and biochemical data laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies. RESULTS: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected individuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hospitalisation (95% CI 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022). CONCLUSIONS: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors. CLINICAL TRIAL REGISTRATION: The protocol was submitted to clinicaltrials.gov (NCT04670419). IMPACT AND IMPLICATIONS: HEV genotype (gt) 3 infections display a wide spectrum of clinical presentations currently ascribed to host factors. Here we examined the role of viral factors on liver disease outcomes by combining viral phylogeny with clinical, biochemical, cytokine, and histological data from 274 Belgian adults infected with HEV presenting between 2010 and 2018. HEV gt 3 clade efg infections were associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. HEV gt3 clade-dependent clinical outcomes call for broad HEV gt3 subtyping in clinical practice and research to help identify those at higher risk for worse outcomes and to further unravel underlying virus-host interactions.
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Virus de la Hepatitis E , Hepatitis E , Adulto , Humanos , Bélgica/epidemiología , Bilirrubina , Genotipo , Hepatitis E/diagnóstico , Hepatitis E/epidemiología , Filogenia , ARN Viral/análisis , Protocolos de Ensayos Clínicos como AsuntoRESUMEN
Alcohol-associated liver disease is a major public health concern globally. Alterations of steroid hormones and gut microbiota were both found in patients with alcohol-associated liver disease. However, their correlation has not been well characterized in these patients. In this study, we measured the level of 30 steroid hormones in serum and fecal samples collected from non-alcoholic controls, patients with alcohol use disorder, and patients with alcohol-associated hepatitis. The profile of serum and fecal steroid hormones was quite different in patients with alcohol-associated hepatitis from that in patients with alcohol use disorder and control subjects. Stronger alterations were observed in male patients than in females. Correlations were found not only between serum steroids and gut bacteria but also between serum steroids and gut fungi. These correlations need to be taken into consideration during the development of treatment strategies for alcohol-associated liver disease.
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BACKGROUND: Intestinal T cells are key in gut barrier function. Their role in early stages of alcohol-associated liver disease (ALD) remain unknown. AIM: To explore the links between intestinal T cells, microbial translocation and ALD METHODS: Patients with alcohol use disorder (AUD) following a rehabilitation programme were compared to subjects with non-alcoholic fatty liver disease (NAFLD) and healthy controls. Clinical and laboratory data (liver stiffness, controlled attenuation parameter, AST, ALT, K18-M65) served to identify AUD patients with isolated steatosis (minimal liver disease) or steatohepatitis/fibrosis (ALD). Serum microbial translocation markers were measured by ELISA, duodenal and plasma levels of sphingolipids by targeted LC-MS. T lymphocytes in duodenal biopsies were characterised by immunohistochemistry, flow cytometry and RNA sequencing on FACS-sorted cells. Mechanisms for T-cell alterations were assessed in vitro. RESULTS: Patients with ALD, but not those with minimal liver disease, showed reduced numbers of duodenal CD8+ T resident memory (TRM) cells compared to controls or patients with NAFLD. TRM transcriptomic analysis, in vitro analyses and pharmacological inhibition of cathepsin B confirmed TRM apoptosis driven by lysosomal membrane permeabilisation and cathepsin B release into the cytosol. Altered lipid metabolism and increased duodenal and plasma sphingolipids correlated with apoptosis. Dihydroceramide dose-dependently reduced viability of TRM. Duodenal TRM phenotypic changes, apoptosis and transcriptomic alterations correlated with increased levels of microbial translocation markers. Short-term abstinence did not reverse TRM cell death in patients with ALD. CONCLUSIONS: Duodenal CD8+ TRM apoptosis related to functional changes in lysosomes and lipid metabolism points to impaired gut adaptive immunity specifically in patients with AUD who developed early ALD.
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Hepatopatías Alcohólicas , Enfermedad del Hígado Graso no Alcohólico , Apoptosis , Biomarcadores/análisis , Linfocitos T CD8-positivos/química , Catepsina B , Humanos , EsfingolípidosRESUMEN
BACKGROUND: Emerging evidence highlights that targeting the gut microbiota could be an interesting approach to improve alcohol liver disease due to its important plasticity. This study aimed to evaluate the effects of inulin supplementation on liver parameters in alcohol use disorder (AUD) patients (whole sample) and in a subpopulation with early alcohol-associated liver disease (eALD). METHODS: Fifty AUD patients, hospitalized for a 3-week detoxification program, were enrolled in a randomized, double-blind, placebo-controlled study and assigned to prebiotic (inulin) versus placebo for 17 days. Liver damage, microbial translocation, inflammatory markers and 16S rDNA sequencing were measured at the beginning (T1) and at the end of the study (T2). FINDINGS: Compared to placebo, AST (ß = 8.55, 95% CI [2.33:14.77]), ALT (ß = 6.01, 95% CI [2.02:10.00]) and IL-18 (ß = 113.86, 95% CI [23.02:204.71]) were statistically significantly higher in the inulin group in the whole sample at T2. In the eALD subgroup, inulin supplementation leads to specific changes in the gut microbiota, including an increase in Bifidobacterium and a decrease of Bacteroides. Despite those changes, AST (ß = 14.63, 95% CI [0.91:28.35]) and ALT (ß = 10.40, 95% CI [1.93:18.88]) at T2 were higher in the inulin group compared to placebo. Treatment was well tolerated without important adverse events or side effects. INTERPRETATION: This pilot study shows that 17 days of inulin supplementation versus placebo, even though it induces specific changes in the gut microbiota, did not alleviate liver damage in AUD patients. Further studies with a larger sample size and duration of supplementation with adequate monitoring of liver parameters are needed to confirm these results. Gut2Brain study: https://clinicaltrials.gov/ct2/show/NCT03803709 FUNDING: Fédération Wallonie-Bruxelles, FRS-FNRS, Fondation Saint-Luc.
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Alcoholismo , Síndrome de Abstinencia a Sustancias , Alcoholismo/complicaciones , Alcoholismo/tratamiento farmacológico , Método Doble Ciego , Heces/microbiología , Humanos , Inulina/uso terapéutico , Hígado , Proyectos Piloto , PrebióticosRESUMEN
Alcohol-related liver disease is a public health care burden globally. Only 10-20% of patients with alcohol use disorder have progressive liver disease. This study aimed to identify lipid biomarkers for the early identification of progressive alcohol-related liver disease, which is a key step for early intervention. We performed untargeted lipidomics analysis in serum and fecal samples for a cohort of 49 subjects, including 17 non-alcoholic controls, 16 patients with non-progressive alcohol-related liver disease, and 16 patients with progressive alcohol-related liver disease. The serum and fecal lipidome profiles in the two patient groups were different from that in the controls. Nine lipid biomarkers were identified that were significantly different between patients with progressive liver disease and patients with non-progressive liver disease in both serum and fecal samples. We further built a random forest model to predict progressive alcohol-related liver disease using nine lipid biomarkers. Fecal lipids performed better (Area Under the Curve, AUC = 0.90) than serum lipids (AUC = 0.79). The lipid biomarkers identified are promising candidates for the early identification of progressive alcohol-related liver disease.
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Alcohol use is a leading cause of chronic liver disease worldwide, and changes in the microbiome associated with alcohol use contribute to patients' risk for liver disease progression. Less is known about the effects of alcohol use on the intestinal viral microbiome (virome) and interactions between bacteriophages and their target bacteria. We studied changes in the intestinal virome of 62 clinically well-characterized patients with alcohol use disorder (AUD) during active alcohol use and after 2 weeks of alcohol abstinence, by extracting virus-like particles and performing metagenomic sequencing. We observed decreased abundance of Propionibacterium, Lactobacillus, and Leuconostoc phages in patients with active AUD when compared with controls, whereas after 2 weeks of alcohol abstinence, patients with AUD demonstrated an increase in the abundance of Propionibacterium, Lactobacillus, and Leuconostoc phages. The intestinal virome signature was also significantly different in patients with AUD with progressive liver disease, with increased abundance of phages targeting Enterobacteria and Lactococcus species phages compared with patients with AUD with nonprogressive liver disease. By performing moderation analyses, we found that progressive liver disease is associated with changes in interactions between some bacteriophages and their respective target bacteria. In summary, active alcohol use and alcohol-associated progressive liver disease are associated with changes in the fecal virome, some of which are partially reversible after a short period of abstinence. Progression of alcohol-associated liver disease is associated with changes in bacteriophage-bacteria interactions.
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Alcoholismo , Bacteriófagos , Microbioma Gastrointestinal , Hepatopatías Alcohólicas , Bacterias/genética , Bacteriófagos/genética , Humanos , Intestinos , Metagenómica , ViromaRESUMEN
PURPOSE: Metabolic dysfunction-associated fatty liver disease-related cirrhosis is possible at the time of bariatric surgery, complicated by further liver decompensation. Hepatic decompensation can also occur in the absence of cirrhosis but the presentation is less clear. METHODS: We analyze the clinical characteristics, histological findings, and management of patients without cirrhosis who developed hepatic decompensation after bariatric surgery in our single tertiary-care hospital. RESULTS: From 2014 to 2019, 6 patients underwent a transvenous liver biopsy for liver decompensation after bariatric surgery. Mean age at diagnosis was 44 years. The time between bariatric surgery and the onset of symptoms varied widely (min. 8 months, max. 17 years). Mean % of weight loss was high at 43%. The clinical presentation was as follows: fatigue and jaundice (5/6), leg edema (3/6), and ascites (1/6). Blood test showed increased transaminases (mean ALT 53 UI/L, mean AST 130 UI/L), bilirubin (mean 6 mg/dL), and INR (mean 1.5) with a low albumin level (mean 27 mg/dL). The hepatic venous pressure gradient was high (mean 10 mmHg). Histology revealed steatosis, hepatocyte ballooning but also portal inflammation with polymorphonuclear cells, and bile duct alterations. Mean fibrosis score was 2. The clinical course was favorable with nutritional support with a mean follow-up of 36 months. CONCLUSION: Liver decompensation in the absence of cirrhosis can occur after bariatric surgery with a highly variable delay. A special histological signature is present with the coexistence of steatosis, bile duct alterations, and portal inflammation. Substantial clinical improvement with appropriate nutritional support seems to be effective.