Dynamic Elevation of Aromatic Amino Acids in Hepatitis C Virus-Induced Cirrhosis After a Standard Meal.

INTRODUCTION: Perturbations in aromatic (AAAs) and branched-chain amino acids (BCAAs) are seen in decompensated liver disease. The aim of this study was to evaluate the dynamic, postprandial relationship between hepatitis C virus-induced liver disease and amino acid concentrations in patients with compensated liver disease. METHODS: Patients infected with hepatitis C virus underwent a baseline liver biopsy to determine Ishak Fibrosis Score and evaluate the liver transcriptome. Patients ate a standard meal and underwent peripheral vein sampling at defined intervals. Quantitative analysis of amino acids was performed using liquid chromatography-tandem mass spectrometry. RESULTS: At baseline, there was no difference in AAA and BCAA concentrations between patients with cirrhosis and non-cirrhotic patients. After a standard meal, AAAs, but not BCAAs, were elevated in patients with cirrhosis compared with non-cirrhotic patients at every time point. The HepQuant SHUNT fraction was significantly higher in patients with cirrhosis and positively correlated with AAA concentration at all time points, but not BCAA. Analysis of the hepatic transcriptome demonstrated greater downregulation of the AAA degradation pathways than the BCAA degradation pathways. DISCUSSION: At baseline, cirrhotic patients with compensated liver disease have adequate reserve liver function to metabolize AAAs and BCAAs. When faced with a metabolic stressor, such as a standard meal, patients with cirrhosis are less able to metabolize the increased load of AAAs. This impairment correlates with portosystemic shunting. Further evaluation of AAA levels in compensated liver disease might further the understanding of the liver-muscle axis and the role it may play in the development of sarcopenia in liver disease.

Taurine-conjugated bile acids and their link to hepatic S1PR2 play a significant role in hepatitis C-related liver disease.

BACKGROUND: Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease. METHODS: Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids. RESULTS: Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2). CONCLUSIONS: Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.

Clinical, Endoscopic, and Histopathologic Gastrointestinal Disease in an American Cohort With Behçet's Disease.

INTRODUCTION: Behçet's disease (BD) is a chronic systemic vasculitis characterized by oral and genital ulcers, uveitis, and skin lesions. Patients with BD may develop gastrointestinal (GI) disease; however, characterization of GI disease in American cohorts is lacking. In this article, we present clinical, endoscopic, and histopathologic GI findings in an American cohort of patients with BD. METHODS: Patients with established BD were evaluated prospectively at the National Institutes of Health. Demographic and clinical data were collected including BD manifestations and GI symptoms. Endoscopy with histopathologic sampling was performed for both clinical and research indications with written consent. RESULTS: Eighty-three patients were evaluated. The majority were female (83.1%) and white (75.9%). Mean age was 36 ± 14.8 years. GI symptoms were reported in 75% of cohort with nearly half of reporting abdominal pain (48.2%) and significant numbers reporting acid reflux, diarrhea, and nausea/vomiting. Esophagogastroduodenoscopy was performed in 37 patients; erythema and ulcers were the most common found abnormalities. Colonoscopy was performed in 32 patients with abnormalities including polyps, erythema, and ulcers. Endoscopy was normal in 27% of esophagogastroduodenoscopies and 47% of colonoscopies. Vascular congestion was demonstrated on the majority of random biopsies throughout the GI tract. Inflammation was not highly prevalent on random biopsies except in the stomach. Wireless capsule endoscopy was performed on 18 patients; ulcers and strictures were the most common abnormalities. DISCUSSION: GI symptoms were common in this cohort of American patients with BD. Endoscopic examination was often normal; however, histopathologic examination demonstrated vascular congestion throughout the GI tract.

Longitudinal multi-omics analyses of the gut-liver axis reveals metabolic dysregulation in hepatitis C infection and cirrhosis.

The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut-liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been associated with an altered gut microbiome; however, how these changes impact metabolism across the gut-liver axis and how this varies with disease severity and time is unclear. Here we used multi-omics analysis of portal and peripheral blood, faeces and liver tissue to characterize the gut-liver axis of patients with HCV across a fibrosis severity gradient before (n = 29) and 6 months after (n = 23) sustained virologic response, that is, no detection of the virus. Fatty acids were the major metabolites perturbed across the liver, portal vein and gut microbiome in HCV, especially in patients with cirrhosis. Decreased fatty acid degradation by hepatic peroxisomes and mitochondria was coupled with increased free fatty acid (FFA) influx to the liver via the portal vein. Metatranscriptomics indicated that Anaerostipes hadrus-mediated fatty acid synthesis influences portal FFAs. Both microbial fatty acid synthesis and portal FFAs were associated with enhanced hepatic fibrosis. Bacteroides vulgatus-mediated intestinal glycan breakdown was linked to portal glycan products, which in turn correlated with enhanced portal inflammation in HCV. Paired comparison of patient samples at both timepoints showed that hepatic metabolism, especially in peroxisomes, is persistently dysregulated in cirrhosis independently of the virus. Sustained virologic response was associated with a potential beneficial role for Methanobrevibacter smithii, which correlated with liver disease severity markers. These results develop our understanding of the gut-liver axis in HCV and non-HCV liver disease aetiologies and provide a foundation for future therapies.