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Background Patients with liver cirrhosis (LC) are prone to gastric mucosa damage. We investigated the alterations of gastric mucosa in LC patients and their possible mechanisms through multi-omics. Results We observed significant gastric mucosa microbial dysbiosis in LC subjects. Gastric mucosal microbiomes of LC patients contained a higher relative abundance of Streptococcus, Neisseria, Prevotella, Veillonella, and Porphyromonas, as well as a decreased abundance in Helicobacter and Achromobacter, than control subjects. The LC patients had higher levels of bile acids (BAs) and long-chain acylcarnitines (long-chain ACs) in serum. The gastric mucosal microbiomes were associated with serum levels of BAs and long-chain ACs. Transcriptome analyses of gastric mucosa revealed an upregulation of endothelial cell specific molecule 1, serpin family E member 1, mucin 2, caudal type homeobox 2, retinol binding protein 2, and defensin alpha 5 in LC group. Besides, the bile secretion signaling pathway was significantly upregulated in the LC group. Conclusions The alterations in the gastric mucosal microbiome and transcriptome of LC patients were identified. The impaired energy metabolism in gastric mucosal cells and bile acids might aggravate the inflammation of gastric mucosa and even exacerbate the Correa's cascade process. The gastric mucosal cells might reduce bile acid toxicity by bile acid efflux and detoxification. Trial registration: ChiCTR2100051070. Keywords: Cirrhosis, Premalignant gastric lesions, Multi-omics integration, Serum bile acids, Ost[alpha]-Ost[beta], Author(s): Ruiguang Ma[sup.1], Qian Li[sup.1], Guoxian Yu[sup.2], Jun Wang[sup.3], Yueyue Li[sup.1], Xinyan Xu[sup.1], Yiqing Zhu[sup.1], Min Dong[sup.1], Yanjing Gao[sup.1], Lixiang Li[sup.1] and Zhen Li[sup.1] Background Liver cirrhosis (LC) is a [...]

Background Cancer-associated fibroblasts (CAFs) are essential stromal components in the tumor microenvironment of hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) infection induces pathological changes such as liver fibrosis/cirrhosis and HCC. The aim of this research was to explore the novel mediators of CAFs to modulate HBV cirrhosis-HCC progression. Methods The single-cell transcriptome data of HCC were divided into subsets, and the significant subset related to fibrotic cells, along with biological function, and clinical information of HCC was revealed by integrated data analyses. The cell communication, cells communicated weight analysis of signaling pathways, and key genes in signaling pathways analysis of significant CAFs subclasses were conducted to discover the novel gene of CAFs. Bioinformatics, vitro and HBV transfection assays were used to verify the novel gene is an important target for promoting the progression HBV cirrhosis-HCC progression. Results Fibroblasts derived from HCC single-cell data could be separated into three cell subclasses (CAF0-2), of which CAF2 was associated with the HCC clinical information. Fibroblasts have opposite developmental trajectories to immune B cells and CD8 + T cells. CAF0-2 had strong interaction with B cells and CD8 + T cells, especially CAF2 had the highest interaction frequency and weight with B cells and CD8 + T cells. Moreover, PTN participated in CAF2-related pathways involved in the regulation of cell communication, and the interactions among CAF2 and PTN contributed the most to B cells and CD8 + T cells. Furthermore, the genes of PTN, SDC1, and NCL from PTN signaling were highest expression in CAF2, B cells, and CD8 + T cells, respectively, and the interaction of PTN- SDC1 and PTN- NCL contributed most to the interaction of CAF2- B cells and CAF2-CD8 + T cells. Bioinformatics and vitro experiments confirm PTN was upregulated in HCC and promoted the proliferation of tumor cells, and HBV infection could initiate PTN to perform cirrhosis-HCC progression. Conclusion Our findings revealed CAF was associated with hepatocarcinogenesis, and the functional importance of B cells and CD8 + T cells in modulating CAF in HCC. Importantly, PTN maybe a novel mediator of CAF to mediate HBV cirrhosis-HCC progression. Keywords: HBV, Cirrhosis, HCC, cancer-associated fibroblast, PTN, Single-cell RNA sequencing, Author(s): Chenhong Lin[sup.1], Yeda Chen[sup.2], Feng Zhang[sup.3], Peng Zhu[sup.4], Liangliang Yu[sup.1] and Wenbiao Chen[sup.2] Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, which accounts for 70-90% [...]

Background Hepatitis B virus (HBV) causes chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. The evolution of human gut microbiota during the progression of HBV-related liver diseases remains unclear. Therefore, we prospectively enrolled patients with HBV-related liver diseases and healthy individuals. Through 16S ribosomal RNA amplicon sequencing, we characterized the gut microbiota of the participants and predicted the functions of microbial communities. Results We analyzed the gut microbiota of 56 healthy controls and 106 patients with HBV-related liver disease [14 with resolved HBV infection, 58 with CHB, and 34 with advanced liver disease (15 with liver cirrhosis and 19 with hepatocellular carcinoma)]. Patients with HBV-related liver disease exhibited a higher degree of bacterial richness (all P < 0.05) than did healthy controls. Beta diversity analyses revealed a distinct clustering pattern between healthy controls and patients with HBV-related liver disease (all P < 0.05). The composition of bacteria (from the phylum level to the genus level) varied across the stages of liver disease. Linear discriminant analysis effect size revealed multiple taxa that differ significantly in abundance between healthy controls and patients with HBV-related liver disease; however, fewer differences were observed among patients with resolved HBV infection, those with CHB, and those with advanced liver disease. The ratio of Firmicutes to Bacteroidetes was increased in all three patient groups compared with the ratio in healthy controls (all P < 0.001). The analysis of the sequencing data by using PICRUSt2 revealed the changes in microbial functions with disease progression. Conclusions The diversity and composition of gut microbiota appear to vary significantly between healthy controls and patients at different stages of HBV-related liver disease. The understanding of gut microbiota may provide novel therapeutic options in these patients. Keywords: Hepatitis B virus, Resolved hepatitis B virus infection, Liver cirrhosis, Hepatocellular carcinoma, Gut microbiota, 16S rRNA sequencing, Metagenomics, Author(s): Meng-Ju Lin[sup.1], Tung-Hung Su[sup.2,3], Chieh-Chang Chen[sup.2], Wei-Kai Wu[sup.4], Shih-Jer Hsu[sup.2], Tai-Chung Tseng[sup.2,3,4], Sih-Han Liao[sup.5], Chun-Ming Hong[sup.6], Hung-Chih Yang[sup.2], Chun-Jen Liu[sup.2,3,7], Ming-Shiang Wu[sup.2] and Jia-Horng Kao[sup.2,3,4,7] Background An estimated 296 [...]

Background Liver cirrhosis is a major public health problem, accounting for high rates of morbidity and mortality worldwide. The cirrhosis etiology is a broad and essential step in planning a treatment strategy. Many recent studies have documented that gut microbiome alterations play a vital role in the development and progression of cirrhosis and its complications. Nevertheless, there is insufficient data on the correlation between liver cirrhosis and gut phageome alterations in patients with advanced liver diseases. This study aimed to analyze the taxonomic structure and functional attributes of the gut phageome in six different etiologies of advanced liver cirrhosis. Methods We first retrieved metagenomic sequencing data from three datasets of fecal samples taken from cirrhotic patients with various etiologies. Subsequently, several bioinformatics pipelines were used to analyze bacteriophage composition and determine their functionality. Results A gene catalog of 479,425 non-redundant genes was developed as a reference to measure gene prevalence. The results of the analysis revealed a few significant differences among the cohorts at the phage species level. However, the alternations were more evident as there were more in-depth analyses of the functional resolution of the gut phageome. Conclusions Our findings suggest that the functional analysis of the gut phageome would provide meaningful markers to predict the progression of liver cirrhosis and facilitate the development of novel treatment approaches. Keywords: Liver cirrhosis, Phageome, Metagenomics, Nonalcoholic fatty liver disease, Author(s): Mohadeseh Naseri[sup.1], Fahimeh Palizban[sup.2], Abbas Yadegar[sup.3], Mohsen Khodarahmi[sup.1,4], Hamid Asadzadeh Aghdaei[sup.5], Hamidreza Houri[sup.3] and Javad Zahiri[sup.6] Introduction The human gut microbiome comprises an extremely diverse and complex community of [...]

Hepatitis delta virus (HDV) is a defective single negative chain RNA virus, as its envelope protein synthesis is dependent on hepatitis B virus (HBV). Studies have consistently shown that coinfection of HBV and HDV is the most serious form of viral hepatitis, with accelerated progression to liver cirrhosis and hepatocellular carcinoma. About 74 million of HBV surface antigen (HBsAg) positive patients worldwide are also co-infected with HDV. Besides, patients with intravenous drug use and high-risk sexual behavior are at higher risk of HDV infection. Therapeutic schedules for HDV are limited, and relapse of HDV has been observed after treatment with pegylated interferon alpha. To reduce the transmission of HDV, all people infected with HBV should be screened for HDV. At present, several serological and molecular detection methods are widely used in the diagnosis of HDV. However, due to the lack of international standards diagnostic results from different laboratories are often not comparable. Therefore, the true prevalence of HDV is still unclear. In this manuscript, we have analyzed various factors influencing the estimation of HDV prevalence. We have also discussed about the advantages and disadvantages of currently available HDV laboratory diagnostic methods, in order to provide some ideas for improving the detection of HDV. Keywords: Hepatitis delta virus, Hepatitis D, Hepatitis B, Prevalence, Diagnostics, Author(s): Lin-Yuan Chen[sup.1], Xiao-Yu Pang[sup.1], Hemant Goyal[sup.2], Rui-Xia Yang[sup.1] and Hua-Guo Xu[sup.1] Introduction Hepatitis Delta virus (HDV) is a blood-borne pathogen that is dependent on the hepatitis B virus (HBV) [...]

White adipose tissue (WAT) dysfunction is generally thought to promote the development of alcoholic liver disease (ALD) in alcoholics by releasing free fatty acids and inflammatory mediators. This explains, at least in part, the synergistic or additive effects of alcohol and obesity on liver disease progression. In this issue of theJCI, Shen et al. establish a previously unrecognized concept that brain alcohol sensing enhances thermogenesis of brown adipose tissue (BAT) through sympathetic nerve activation. BAT functions as hepatoprotective machinery to counteract the development of ALD, implying a therapeutic potential of BAT activity modulation for the treatment of ALD., Adipose tissue in alcoholic liver disease Alcoholic liver disease (ALD) is a leading cause of chronic liver diseases that ranges from fatty liver to steatohepatitis, cirrhosis, and liver cancer (1). [...]

Introduction Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized. Methods Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome. Results Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of Enterobacteriaceae > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant Enterobacteriaceae) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis. Conclusion The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of Enterobacteriaceae during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon. Keywords: Quinolones, Multidrug-resistance, Infections, Bacterial abundance, Enterobacteriaceae, Author(s): Marcus M. Mücke[sup.1], Sabrina Rüschenbaum[sup.1,2], Amelie Mayer[sup.1], Victoria T. Mücke[sup.1], Katharina M. Schwarzkopf[sup.1], Stefan Zeuzem[sup.1], Jan Kehrmann[sup.3], René Scholtysik[sup.4] and Christian M. Lange[sup.1,2] Introduction Infections in cirrhosis often lead [...]

Author(s): Manikankana Bandopadhyay[sup.1] and Mausumi Bharadwaj[sup.1] Background Globally, 247 million people are affected with chronic Hepatitis B virus (HBV) infection [1]. Although there is availability of operative vaccine for HBV, [...]

The serpinopathies result from the ordered polymerization of mutants of members of the serine proteinase inhibitor (serpin) superfamily. These polymers are retained within the cell of synthesis Where they cause a toxic gain of function. The serpinopathies are exemplified by inclusions that form with the common severe Z mutant of [[alpha].sub.1]-antitrypsin that are associated with liver cirrhosis. There is considerable controversy as to the pathway of serpin polymerization and the structure of pathogenic polymers that cause disease. We have used synthetic peptides, limited proteolysis, monoclonal antibodies, and ion mobility-mass spectrometry to characterize the polymerogenic intermediate and pathological polymers formed by Z [[alpha].sub.1]-antitrypsin. Our data are best explained by a model in which polymers form through a single intermediate and with a reactive center loop-[beta]-sheet A linkage. Our data are not compatible with the recent model in which polymers are linked by a [beta]-hairpin of the reactive center loop and strand 5A. Understanding the structure of the serpin polymer is essential for rational drug design strategies that aim to block polymerization and so treat [[alpha].sub.1]-antitrypsin deficiency and the serpinopathies. alpha-1-antitrypsin deficiency | protein folding | serpins | polymers | cirrhosis doi/ 10.1073/pnas.1004785107

Choi SS, Omenetti A, Witek RP, Moylan CA, Syn W, Jung Y, Yang L, Sudan DL, Sicklick JK, Michelotti GA, Rojkind M, Diehl AM. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol 297:G1093-G1106, 2009. First published October 8, 2009; doi: 10.1152/ajpgi.00292.2009.--Myofibroblastic hepatic stellate cells (MF-HSC) are derived from quiescent hepatic stellate cells (Q-HSC). Q-HSC express certain epithelial cell markers and have been reported to form junctional complexes similar to epithelial cells. We have shown that Hedgehog (Hh) signaling plays a key role in HSC growth. Because Hh ligands regulate epithelial-to-mesenchymal transition (EMT), we determined whether Q-HSC express EMT markers and then assessed whether these markers change as Q-HSC transition into MF-HSC and whether the process is modulated by Hh signaling. Q-HSC were isolated from healthy livers and cultured to promote myofibroblastic transition. Changes in mRNA and protein expression of epithelial and mesenchymal markers, Hh ligands, and target genes were monitored in HSC treated with and without cyclopamine (an Hh inhibitor). Studies were repeated in primary human HSC and clonally derived HSC from a cirrhotic rat. Q-HSC activation in vitro (culture) and in vivo (C[Cl.sub.4]-induced cirrhosis) resulted in decreased expression of Hh-interacting protein (Hhip, an Hh antagonist), the EMT inhibitors bone morphogenic protein (BMP-7) and inhibitor of differentiation (Id2), the adherens junction component E-cadherin, and epithelial keratins 7 and 19 and increased expression of Gli2 (an Hh target gene) and mesenchymal markers, including the mesenchyme-associated transcription factors Lhx2 and Msx2, the myofibroblast marker [alpha]-smooth muscle actin, and matrix molecules such as collagen. Cyclopamine reverted myofibroblastic transition, reducing mesenchymal gene expression while increasing epithelial markers in rodent and human HSC. We conclude that Hh signaling plays a key role in transition of Q-HSC into MF-HSC. Our findings suggest that Q-HSC are capable of transitioning between epithelial and mesenchymal fates. bone morphogenetic protein-7; cyclopamine; fibrosis; proliferation; regeneration doi: 10.1152/ajpgi.00292.2009

Inappropriate vasopressin (AVP) release causes dilutional hyponatremia in many pathophysiological states such as cirrhosis. The central molecular mechanisms that mediate inappropriate AVP release are unknown. We tested the hypothesis that changes in the expression or trafficking of TRPV4 in the central nervous system may contribute to inappropriate AVP release in the bile duct ligation (BDL) model of cirrhosis in the rat. Four weeks after surgery, BDL rats demonstrated significantly increased plasma vasopressin and plasma renin activity (PRA), hypervolemia, and decreased plasma osmolality. These effects were blocked by providing BDL rats with 2% saline to drink for 15 days. TRPV4 protein expression was significantly increased in brain punches from BDL rats containing the supraoptic nucleus (SON) of the hypothalamus (100% [+ or -] 11 to 157% [+ or -] 4.8), and this effect was blocked in BDL rats given saline. Immunohistochemistry demonstrated a significant increase in TRPV4-positive cells and the percentage of AVP neurons that also were TRPV4-positive in the SON of BDL rats. In the hypothalamus of BDL rats, TRPV4 lipid raft association increased compared with sham (from 100% [+ or -] 2.1 to 326.1% [+ or -] 16). This effect was significantly attenuated in BDL rats given 2% saline to drink (174% [+ or -] 11). In the brain stem, TRPV4 lipid raft association was reduced by BDL and inversely related to plasma AVP and PRA. We speculate that changes in TRPV4 expression and compartmentalization within lipid rafts could contribute to a feed-forward mechanism related to AVP release in cirrhosis. renin-angiotensin; lipid rafts; supraoptic nucleus; hypothalamus

Liver cirrhosis is a catabolic disease associated with a high incidence of insulin resistance and diabetes mellitus. Pre-B cell colony-enhancing factor/nicotinamide phosphoribosyltransferase/visfatin has been characterized as a novel adipokine with a potential role in glucose metabolism and nicotinamide dinucleotide (NAD) generation. We studied plasma levels and metabolic relevance of visfatin in 19 patients with cirrhosis and 19 body mass index-, age-, and sex-matched controls. In addition, hepatic mRNA expression was assessed by qPCR in livers of seven patients with cirrhosis and four controls. Circulating visfatin was 78% lower in cirrhotics (P < 0.001) and decreased with worsening of the clinical stage of liver disease. Hepatic visfatin secretion decreased with clinical stage (P < 0.05) and reduced liver function (P = 0.01). Consistent with these data, hepatic visfatin mRNA expression was significantly lower in cirrhotic livers (P < 0.05). Circulating visfatin in cirrhosis was correlated with body cell mass (r = 0.72, P < 0.01) as well as with body fat mass (r = 0.53, P < 0.05) but not with plasma glucose, insulin, the degree of insulin resistance, or whole body glucose oxidation rates. Higher visfatin levels were associated with higher hepatic glucose production (r = 0.53, P < 0.05) and also with a higher arterial ketone body ratio (KBR) (r = 0.48, P < 0.05), an indicator of increased hepatic NAD generation. In conclusion, circulating visfatin levels are significantly decreased in liver cirrhosis, presumably attributable to decreased hepatic expression and production. Plasma visfatin in cirrhosis is not associated with insulin resistance but correlates with hepatic glucose production and the arterial KBR, indicating a potential link between the NAD-generating properties of visfatin and metabolism. adipokines; human; metabolism; nicotinamide phosphoribosyltransferase; pre-B cell colony-enhancing factor

The vasopressin analog terlipressin is believed to cause vasoconstriction selectively by [V.sub.1] receptor stimulation. However, a possible antidiuretic effect by [V.sub.2] receptor stimulation has never been ruled out. Twenty-two patients with ascites, including seven with refractory ascites, were included. The subjects were studied during a 400 ml/h oral water load before and after infusion of 2 mg of terlipressin (18 patients) or placebo infusion (4 patients). Effects on the V2 receptors were assessed by evaluating aquaporin (AQP)2 excretion, free water clearance ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]),urine osmolality ([U.sub.osm]), and fractional distal water excretion (DFe[H.sub.2]O). After terlipressin the excretion of AQP2 increased by 89% [144 ng/mmol creatinine, 95% confidence interval (CI) 73-214 ng/mmol creatinine, P = 0.001]. [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] decreased 1.05 ml/min (from 0.17 to -0.89 ml/min, P = 0.001), and DFe[H.sub.2]O decreased 37% (19 vs. 12; 95% CI 2-11, P = 0.01). [U.sub.osm] increased by 27% (93 mosmol/kg[H.sub.2]O, 95% CI 23-164 mosmol/kg[H.sub.2]O, P = 0.02). Plasma sodium decreased 1.1 mmol/1 (P < 0.01). An increase in AQP2 excretion and a decrease in [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and distal water excretion after terlipressin despite water loading is-a clear indication of activation of the antidiuretic system ([V.sub.2] receptor effect). aquaporin-2; vasopressin; hepatorenal syndrome; cirrhosis; ascites

Cirrhosis is associated with marked cardiovascular disturbances. These include hyperdynamic circulation characterized by reduced peripheral vascular resistance and mean arterial pressure and increased cardiac output. Despite the baseline increase in cardiac output, ventricular responsiveness to stimuli is blunted. A number of cellular signaling pathways have been shown to contribute to these abnormalities, including central nervous system cardiovascular dysregulation and humoral factors such as nitric oxide. Endogenous and exogenous cannabinoids have significant cardiovascular effects. Recent evidence suggests that increased activity of the endocannabinoid system at multiple levels contributes to development of both cardiac and vascular changes in cirrhosis. This brief review surveys recent in vivo and in vitro findings in an attempt to highlight the areas of agreement and areas of controversy in the field. The endocannabinoid system affects key cardiovascular regulators, including the autonomic nervous system, cardiac muscle, and vascular smooth muscle. The interplay among these modes of action further complicates interpretation of the in vivo findings. The broad range of cardiovascular actions of endocannabinoids provides ample opportunities for pharmacological manipulation. At the same time, it increases the possibility of undesirable side effects, which need to be carefully evaluated in long-term studies. portal hypertension; vanilloid; anandamide; cirrhotic cardiomyopathy

We explored the mechanism(s) of increased aromatic amino acids concentrations in liver cirrhosis using phenylalanine (Phe) and tyrosine (Tyr) isotope infusions in male patients with compensated cirrhosis (five in Child Class A, three in B) and in eight matched healthy controls, in both postabsorptive and fed states. After a baseline period, a standard liquid mixed meal was fed continuously over 4 h. Both a 'plasma' and an intracellular model were employed. In the patients, steady-state Phe and Tyr concentrations were ~30-50% greater, and rates of Phe appearance (Ra) (plasma model), Tyr Ra, and Phe hydroxylation (Hy; both models) were ~25 to > 100% greater than in controls in both states. Meal ingestion increased (P < 0.05 or less vs. basal) Phe and Tyr concentrations, Phe and Tyr Ra, Phe Hy, and % Tyr Ra not deriving from Hy in both groups. Hy and Tyr Ra remained > 50% greater (P < 0.04 to P < 0.01) in patients, whereas Phe Ra was more modestly increased. Phe utilization for protein synthesis increased similarly in both groups. Tyr clearance was normal, whereas Phe clearance tended to be lower (P = 0.09, intracellular model) in the patients. In summary, in compensated liver cirrhosis studied under fasted and fed states, 1) Tyr Ra is increased; 2) Phe Hy and Phe Ra (plasma model) are increased; 3) Tyr clearance is normal; and 4) Phe clearance is slightly decreased. In conclusion, in cirrhosis increased total tyrosine Ra and hydroxylation contribute to fasting and postmeal hypertyrosinemia, whereas the mechanism(s) responsible for the hyperphenylalaninemia may include both increased production and decreased disposal. compensated liver cirrhosis; mixed meal; tyrosine hydroxylation; stable isotopes