Increasing plasma bile salt levels with Bulevirtide alleviates DSS-induced colitis and LPS-induced inflammation

Abstract

Background & AimsBulevirtide, 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. MethodsThe 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. ResultsIn 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-1{beta}, IL-18 and cleaved-IL-1{beta} 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. ConclusionThese 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/719641v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@38efbeorg.highwire.dtl.DTLVardef@3e09borg.highwire.dtl.DTLVardef@8f1262org.highwire.dtl.DTLVardef@100179c_HPS_FORMAT_FIGEXP M_FIG C_FIG SynopsisInhibition 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.