No effect of rifaximin on soluble CD163, mannose receptor or type III and IV neoepitope collagen markers in decompensated cirrhosis: Results from a randomized, placebo controlled trial

PLoS One. 2018 Sep 5;13(9):e0203200. doi: 10.1371/journal.pone.0203200. eCollection 2018.

Abstract

Background and aims: Macrophages play a significant role in chronic liver disease as reflected by elevated soluble (s)CD163 and mannose receptor (sMR) levels and associated with liver disease severity and prognosis. Extracellular matrix remodelling associated with fibrogenesis may be affected by systemic inflammation induced by bacterial translocation. Therefore, we aimed to investigate the effect of rifaximin-α, an antibiotic with effect on gut bacteria, on sCD163, sMR, and collagen metabolites.

Methods: Fifty-four clinically stable patients with decompensated cirrhosis were randomized to 4 weeks treatment with rifaximin-α (n = 36) or placebo (n = 18). Macrophage markers sCD163, sMR and markers of collagen fibrogenesis (C3M and C4M) and formation (PRO-C3 and P4NPS7) were analysed in plasma before and after treatment.

Results: sCD163 and sMR levels were associated with liver disease severity (MELD score, sCD163 rho = 0.47, p<0.001 and sMR rho = 0.37, p = 0.005). There was no effect of Rifaximin-α on sCD163 levels (median (range) sCD163 5.64(2.02 to 10.8) at baseline versus 4.42(1.98 to 8.92) at follow-up in the rifaximin-α group and 4.85 (2.29 to 12.1) at baseline versus 4.32 (1.98 to 12.4) at follow-up in the placebo-group), p = 0.34); nor sMR levels, p = 0.34. Also in patients with elevated lipopolysaccharide binding protein (> 5.9 μg/ml, 38 patients) there was no effect of rifaximin-α on sCD163 (p = 0.49) or sMR levels (p = 0.32).

Conclusion: We confirmed that macrophage activation markers sCD163 and sMR are directly associated to liver disease severity (MELD score). However, rifaximin-α has no effect on sCD163, sMR or collagen markers in decompensated cirrhosis and does therefore not seem to interfere with macrophage activation or fibrogenesis.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, CD / blood
  • Antigens, Differentiation, Myelomonocytic / blood
  • Biomarkers / blood
  • Collagen Type III / blood
  • Collagen Type IV / blood
  • Double-Blind Method
  • Female
  • Gastrointestinal Agents / therapeutic use*
  • Humans
  • Lectins, C-Type / blood
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / drug therapy*
  • Male
  • Mannose-Binding Lectins / blood
  • Middle Aged
  • Receptors, Cell Surface / blood
  • Rifaximin / therapeutic use*
  • Severity of Illness Index
  • Treatment Outcome

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Biomarkers
  • CD163 antigen
  • Collagen Type III
  • Collagen Type IV
  • Gastrointestinal Agents
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • mannose receptor
  • Rifaximin

Grant support

This trial was funded by The Research Foundation of The Capital Region of Denmark, Novo Nordisk Foundation (NNF13OC0006561), Aase & Ejnar Danielsens Foundation, Amager and Hvidovre Hospital Research Foundation. The funders provided support in the form of salaries for authors (NK and JSP), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Norgine Denmark A/S delivered drugs (XIFAXAN, Norgine Denmark A/S, for Alfasigma S.p.A., Bologna, Italy) and the placebo as an unrestricted grant. This funder did not provide support in the form of salaries, and had no additional role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Nordic Bioscience provided support in the form of salaries for authors NSG, DJL, MJN and MAK, and analyzed neoepitope markers free of charge. NSG, DJL, MJN, MAK did not have any role in the study design or data collection, but performed analysis, and participated in preparing the manuscript, writing discussion and revision of the manuscript.