Increasing plasma bile salt levels with Bulevirtide alleviates DSS-induced colitis and LPS-induced inflammation
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Background & Aims Bulevirtide, a viral entry inhibitor used to treat chronic hepatitis delta virus (HDV) infection, targets the hepatic bile salt transporter Na + -Taurocholate Co-transporting Polypeptide (NTCP). As Bulevirtide displays preclinical potential to mitigate cholestatic liver injury, NTCP inhibition is currently explored as treatment for primary sclerosing cholangitis (PSC), a condition frequently associated with colitis. Here, we investigated the immunomodulatory effects of Bulevirtide in lipopolysaccharide (LPS)-induced inflammation and dextran sodium sulfate (DSS)-induced colitis in mice. Methods The immunomodulatory properties of the bile salt taurochenodeoxycholic acid (TCDC) were investigated in LPS-challenged mouse bone marrow-derived macrophages (BMDM) and human BLaER1 macrophages. The therapeutic efficacy of Bulevirtide against LPS-induced inflammation and DSS-induced colitis was evaluated in Slco1a/1b -/- FVB and C57BL/6J mice, which recapitulate human bile salt dynamics. Results In BMDMs, TCDC reduced pro-inflammatory tumor necrosis factor alpha (TNF), increased anti-inflammatory interleukin (IL)-10, and suppressed inflammasome activation, as evidenced by reduced IL-1β, IL-18 and cleaved-IL-1β levels. Consistently, TCDC also reduced TNF and IL1B expression in human BLaER1 macrophages. In both FVB and C57BL/6J Slco1a/1b -/- mice , Bulevirtide increased plasma bile salt levels at least 30-fold. This systemic elevation of bile salts reduced plasma TNF and increased IL-10 in LPS-treated mice. Moreover, Bulevirtide attenuated DSS-induced colitis, evidenced by reduced disease scores and reduced intestinal Tnf expression. Conclusion These findings highlight the anti-inflammatory effects of bile salts in preclinical models of colitis and support NTCP inhibition as a future therapeutic strategy to ameliorate both cholestasis and colitis in PSC. Graphical abstract Synopsis Inhibition of the Na + -Taurocholate Co-transporting Polypeptide using Bulevirtide induces systemic bile salt elevation and mitigates acute inflammation and colitis in mice. These findings support clinical evaluation of Bulevirtide in primary sclerosing cholangitis with protective effects against cholestasis and colitis.
Authors 15
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Leiden University Center for Infectious Diseases, subdepartment Research, Systemic Immunometabolism group, Leiden University Medical Center, Leiden, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Department of Medical Biochemistry, Amsterdam UMC - location University of Amsterdam; Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes; Amsterdam Institute for Infection and Immunity, Inflammatory diseases; Amsterdam University Medical Center, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Department of Medical Biochemistry, Amsterdam UMC - location University of Amsterdam; Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes; Amsterdam Institute for Infection and Immunity, Inflammatory diseases; Amsterdam University Medical Center, Amsterdam, The Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Leiden University Center for Infectious Diseases, subdepartment Research, Systemic Immunometabolism group, Leiden University Medical Center, Leiden, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Stan F.J. van de Graaf corresponding
Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Center, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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