1414 GUT MICROBIOTA REGULATES BILE ACID METABOLISM BY REDUCING THE LEVELS OF TAURO-BETAMURICHOLIC ACID, A NATURALLY OCCURRING FXR ANTAGONIST

1414 GUT MICROBIOTA REGULATES BILE ACID METABOLISM BY REDUCING THE LEVELS OF TAURO-BETAMURICHOLIC ACID, A NATURALLY OCCURRING FXR ANTAGONIST

LATE BREAKING ABSTRACTS of MCB (1000 mg bid) and DNVr (100 mg/100 mg bid) plus RBV (1000/1200 mg daily) for 12/24 weeks (Arm A), or MCB and DNVr plus ...

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LATE BREAKING ABSTRACTS of MCB (1000 mg bid) and DNVr (100 mg/100 mg bid) plus RBV (1000/1200 mg daily) for 12/24 weeks (Arm A), or MCB and DNVr plus placebo for 12/24 weeks (Arm B). Patients with HCV RNA ≤43 IU/mL at week 2 and remaining suppressed (HCV RNA ≤15 IU/mL) at week 10 were re-randomised at week 12 to discontinue treatment or continue assigned regimens until week 24. Due to unacceptable relapse rates, randomisation to 12 weeks of treatment was stopped prematurely, and patients assigned to 24 weeks of treatment in Arm B were offered follow-on Peg-IFNa/RBV therapy. Results: Overall, 169 patients received study drug. Demographics were balanced between arms; 67% of patients were HCV G1a and 69% had an IL28B non-CC genotype. Treatment with MCB and DNVr +/− RBV was safe and well tolerated, with only 4 serious adverse events and 2 discontinuations due to adverse events reported across arms. Breakthrough was associated with DNVresistant virus; 1 patient had dual MCB (NS5B S282T) and DNV (NS3/4A R155K)-resistant virus. At week 4, 91% of patients in Arm A and 93% in Arm B had HCV RNA ≤15 IU/mL. In patients scheduled to receive 24 weeks of MCB and DNVr with RBV in Arm A (excluding 1 discontinuation due to patient choice and 2 pending follow-up; n = 63), the SVR-8 rate was 71% (15/21) in G1b and 26% (11/42) in G1a patients (41% [26/63] overall). Conclusions: An SVR-8 rate of 71% was observed among G1b patients receiving 24 weeks of MCB and DNVr plus RBV treatment. Considering its promising efficacy in G1b patients and its excellent tolerability and safety profile, this interferon-free regimen warrants further study. Acknowledgement: Funded by Roche 1413 A FREQUENT PNPLA3 VARIANT PREDICTS DISEASE COURSE IN PRIMARY SCLEROSING CHOLANGITIS D. Gotthardt1 , K. Friedrich1 , C. Rupp1 , N. Steinebrunner1 , P. Sauer1 , K.H. Weiss1 , A. Stiehl1 , P. Schirmacher2 , W. Stremmel1 , H. Runz3 . 1 Innere Medizin IV, Universit¨ atsklinik Heidelberg, 2 Dept. of Pathology, 3 Dept. of Human Genetics, University of Heidelberg, Heidelberg, Germany E-mail: [email protected] Introduction: Primary sclerosing cholangitis (PSC) is caused by chronic inflammation of the bile ducts and can progress to liver cirrhosis, liver failure or cholangiocarcinoma. The rs738409 variant (I148M) of the PNPLA3 gene is known to be associated with alcoholic and non-alcoholic liver disease and we evaluated its impact on the disease course of PSC. Methods: I148M polymorphism was screened in 121 PSC patients in a long-term prospective study cohort (treated with UDCA and endoscopically in presence of dominant stenosis (DS), ESLD patients excluded at baseline, follow-up up to 25 years) and in 83 PSC patients who had undergone endoscopic retrograde cholangiography (ERC) at our institute. Carriers of one or two mutated alleles were combined into one group. Indication for liver transplantation (OLT) was decompensated cirrhosis. Kaplan-Meier analysis was used defining OLT or death as events. Expression analysis was performed by RT-PCR in biliary tract samples from humans and mice. Results: In the prospective study cohort PNPLA3 genotype was in Hardy-Weinberg equilibrium, and actuarial survival free of OLT was significantly reduced (p = 0.011) in carriers of the I148M variant (mean 13.9±1 yrs; 95% CI: 11.80–16.02) compared to non-carriers (mean 19.3±1 yrs; 95% CI: 17.32–21.43). Patients with a DS showed markedly reduced actuarial survival free of OLT (p = 0.004) from the time-point of first dilatation when carrying the I148M variant (mean 9.6±0.9 yrs; 95% CI: 7.77–11.53) compared to WT patients (mean 16.2±1.2 yrs; 95% CI: 13.72–18.69). No significant difference in Mayo risk score at baseline. Evaluation of all 204 PSC patients that had received ERC at our institute showed that carriers of the I148M S556

polymorphism were at significantly higher risk of developing DS (WT 72/118 (61.0 %) vs. mutated 64/86 (74.4 %); p = 0.045). PNPLA3 expression could be detected in tissue from the biliary tract. Conclusions: The I148M variant of the PNPLA3 gene is a risk factor for PSC patients and it plays a substantial role in cholestatic liver diseases. This might lead to novel diagnostic and therapeutic approaches in PSC. Genetic testing for the common PNPLA3 variant might become routine practice. 1414 GUT MICROBIOTA REGULATES BILE ACID METABOLISM BY REDUCING THE LEVELS OF TAURO-BETAMURICHOLIC ACID, A NATURALLY OCCURRING FXR ANTAGONIST 2 2 S. Islam1 , J. Felin1 , S. Jantti ¨ , T. Hyotyl ¨ ainen ¨ , A. Wahlstrom ¨ 1, 1 H.-U. Marschall1 , K. Bamberg3 , B. Angelin4 , M. Oreˇsiˇc2 , F. Backhed ¨ . 1 Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; 2 VTT Technical Research Centre of Finland, Espoo, Finland; 3 AstraZeneca R&D, M¨ olndal, 4 Department of Endocrinology, Metabolism & Diabetes C2–94, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden E-mail: [email protected] Background and Aims: Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. We investigated how the gut microbiota affects bile acid metabolism. Furthermore, the nuclear receptor farnesoid-x-receptor (FXR) is known to play a key role in the regulation of bile acid synthesis and homeostasis. We therefore investigated if the effects of the gut microbiota on bile acid homeostasis are mediated through FXR. Methods: Bile acids were measured in germ-free (GF) and conventionally raised (CONV-R) mice using UPLC-MS. Fxr-deficient mice were rederived as GF in order to study the impact of the gut flora on bile acid metabolism through this nuclear receptor. Quantitative real-time PCR was used to determine expression of FXR target genes in the liver and distal ileum. a- and b-muricholic acid and their respective taurine conjugates were tested for direct FXR activity in a co-activator recruitment assay. Results: In the presence of a gut microbiota, mice have a smaller total bile acid pool, with specific reductions in the primary bile acid muricholic acid rather than cholic acid. This difference can be attributed to reduced hepatic expression and activity of cholesterol7a-hydroxylase (CYP7A1) and is associated with increased ileal fibroblast growth factor-15 (FGF15) expression. Rederivation of Fxrdeficient mice as GF showed that the gut microbiota regulates expression of FGF15 in the ileum and CYP7A1 in the liver through this nuclear receptor. Since GF mice have elevated bile acid levels, in particular tauroconjugated b-muricholic acid (TbMCA), but reduced FXR activation we hypothesized that GF bile contained a FXR antagonist. In agreement with this hypothesis we identified muricholic acids as endogenous FXR antagonists. Conclusions: We have demonstrated that the gut microbiota has a profound systemic effect on bile acid metabolism. We propose that the gut microbiota modulates bile acid synthesis by changing the bile acid pool composition and by alleviating FXR inhibition in the small intestine. In summary, we demonstrate that the microbial suppression of biosynthetic genes in the liver is consistent with increased FXR-dependent activation of FGF15 in the ileum due to reduced TbMCA mediated inhibition of this nuclear receptor.

Journal of Hepatology 2012 vol. 56 | S549–S560