Different Probiotic Strains in Experimentally Induced Liver Cirrhosis in Rats: Intestinal Barrier Homeostasis as a Key Point to Attenuate Fibrosis?

ORAL PRESENTATIONS difference (MAD) 1.69 kg, CI 0.40–2.97 kg, p = 0.021). Total lean mass was similarly higher in the active group (MAD 4.74 kg, CI 1.75– 7.74 kg, p = 0.008). Fat mass was lower in the actively treated group (MAD−4.34 kg, CI−2.04 to −6.64 kg, p < 0.001). Bone mineral density was significantly higher at the femoral neck and total bone mass were both significantly higher in the active group (MAD in T score 0.287 points, CI 0.140–0.4340.140–0.434, p < 0.001; (MAD in bone mass 0.08 kg, CI 0.01–0.15 kg, p = 0.009). Haemoglobin was significantly higher in actively treated patients (MAD 10.2 g/L, CI 1.50–18.9 g/L, p = 0.041) and HbA1c was lower (MAD −0.35%, CI −0.05 to −0.54, p = 0.028). No serious adverse effects were reported. There were more deaths on placebo (25.5%) than active treatment (16%) but this was not significant ( p = 0.352). Conclusions: Testosterone therapy in men with cirrhosis and low baseline testosterone levels safely improves muscle mass, bone mass and haemoglobin, and reduces fat mass and HbA1c. This is a promising new therapy for systemic complications of cirrhosis that targets a specific hormonal imbalance in men with cirrhosis. PS011 IN TOXIC CIRRHOTIC RATS, THE FXR AGONIST OBETICHOLIC ACID REDUCES LIVER FIBROSIS INDIRECTLY VIA AN ANTIINFLAMMATORY EFFECT IN LIVER SINUSOIDAL ENDOTHELIAL CELLS AND KUPFFER CELLS L.D. Verbeke1, I. Mannaerts2, R. Schierwagen3, O. Govaere4, S. Klein3, I.V. Elst1, P. Windmolders1, R. Farre5,6, M. Wenes7,8, M. Mazzone7,8, F. Nevens1, L. van Grunsven2, J. Trebicka3, W. Laleman1. 1Hepatology, University of Leuven, Leuven; 2Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussels, Belgium; 3Department of Internal Medicine I, University of Bonn, Bonn, Germany; 4Translational Cell and Tissue Research, Department of Imaging and Pathology; 5Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; 6Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos II, Barcelona, Spain; 7Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, University of Leuven; 8Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, VIB, Leuven, Belgium E-mail: [email protected] Background and Aims: The FXR agonist obeticholic acid (OCA) is reported to reduce hepatic fibrosis in animal models of biliary cirrhosis and patients with non-alcoholic fatty liver disease. The underlying mechanism is largely unknown. Methods: Toxic cirrhosis was induced in rats by 18 week thioacetamide (TAA) administration. OCA or placebo was given either during the last 4 weeks of cirrhosis induction or 4 weeks after the establishment of cirrhosis. At sacrifice, fibrosis was measured by image analysis and hydroxyproline assay. A large panel of cytokines involved in hepatic fibrosis, inflammation and cell turn-over as well as NF-κβ activity was investigated in the hepatic tissue of all experimental groups (RT-PCR, Western Blot, ELISA, immunohistochemistry). This was compared to in vitro findings in isolated murine hepatic stellate cells (HSC), Kupffer cells (KC), hepatocytes (HEP) and liver sinusoidal endothelial cells (LSEC), in either inactive phenotype, or tumor necrosis factor alpha (TNF-α) or endotoxin (LPS)-stimulated phenotype, both in the presence or absence of OCA. Results: OCA significantly inhibited the development of hepatic fibrosis during TAA intoxication and reversed fibrosis in established cirrhotic rats. This was associated with decreased expression of proinflammatory (MCP-1, F4/80) and pro-fibrotic (CTGF, TGF-β1, TIMP-1) cytokines as well as decreased markers of hepatic cell turn-over such as caspase-3. While this was associated with decreased markers of HSC activation in vivo such as α-SMA, a direct effect of OCA on HSC was ruled out in vitro. In isolated KC and LSEC however, OCA dose-dependently prevented the LPS- or TNF-α-induced expression of pro-inflammatory cytokines such as monocyte chemo-attractant

protein-1 (MCP-1), known to drive the activation of HSC. The observed anti-inflammatory effect was associated with an OCA-induced inhibition of the common inflammatory NF-κβ pathway via increased IκBα. Conclusions: OCA reduces hepatic fibrosis both preventively and therapeutically in toxic cirrhotic rats. This is associated with decreased HSC activation related to an indirect anti-inflammatory effect on KC and LSEC. PS012 DIFFERENT PROBIOTIC STRAINS IN EXPERIMENTALLY INDUCED LIVER CIRRHOSIS IN RATS: INTESTINAL BARRIER HOMEOSTASIS AS A KEY POINT TO ATTENUATE FIBROSIS? D. Shi1, L. Li1, D. Fang1, L. Lv1, W. Wu1, F. Guo1. 1Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University, Hangzhou, China E-mail: [email protected] Background and Aims: Intestinal barrier dysfunction has been described in liver cirrhosis and intervention in the gut ecosystem is considered as a potential strategy to treat liver diseases and their complications. The aim of this study was to evaluate the effect of a long-period microbial intervention with different probiotic strains on gut-live axis in rats with experimental cirrhosis. Methods: Cirrhosis was induced by weight-controlled subcutaneous administration of carbon tetrachloride. Ninety-eight Sprague Dawley rats were given intragastric supplements of Lactobacillus salivarius LI01, Pediococcus pentosaceus LI05, Lactobacillus rhamnosus GG, Clostridium butyricum or Bacillus Licheniformis for 13 weeks. One week after the last doze of CCL4, samples were collected to determine bacterial translocation, intestinal barrier, intestinal flora, liver function, liver fibrosis and inflammatory response. Results: Rats in L.salivarius LI01 or P.pentosaceus LI05 groups have a higher survival rate than those in the other treatment groups. Treatment with P.pentosaceus LI05 significantly decreased the elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidease (GGT). The incidence of bacterial translocation was much lower in C.butyricum group (4/7, 57%), LI01 group (4/11, 36%), LI05 group (4/9, 44%), L.rhamnosus GG group (4/8, 50%) than positive control group (8/ 8, 100%). Gut barrier integrity markers (ZO-1, b-defensin-1, occludin), ileum histology score and intestinal mucosal ultrastructure were significantly improved in rats receiving L. salivarius LI01 or P. pentosaceus LI05. Moreover, the strains showed significant effect on structural liver damage, as determined by histological evaluation, alpha-smooth muscle actin distribution, profibrogenic gene expression levels. 16s rDNA sequencing analysis of cecal contents revealed a higher microbial diversity and richness as well as a better composition of microbial communities in LI01 or LI05 group. The protective effect of L.salivarius LI01 or P.pentosaceus LI05 on gut injury and liver fibrosis may be correlated with a normalized inflammatory cytokines (TNF-a, IL-6, IL-17, IL-1b) and regulated toll-like receptors (TLR2, TLR4, TLR5, TLR7, TLR9) in both liver and ileum. Conclusions: A long-period microbial intervention with L. salivarius LI01 or P. pentosaceus LI05 strains can maintain a homeostasis of intestinal flora to improve gut barrier integrity and ameliorate liver fibrosis in rats with experimental cirrhosis. PS013 EARLY USE OF TIPS AND OUTCOMES IN PATIENTS WITH CIRRHOSIS AND ACUTE ESOPHAGEAL VARICEAL BLEEDING: ANALYSIS OF THE U.S. NATIONWIDE INPATIENT SAMPLE DATABASE, 2000–2010 B. Njei1. 1Section of Digestive Diseases, Yale University, New Haven, United States E-mail: [email protected] Background and Aims: Recent evidence suggest that TIPS placement as primary therapy within 72 hours after esophageal variceal

Journal of Hepatology 2016 vol. 64 | S133–S158

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