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

Nina Kimer; Natasja Stæhr Gudmann; Julie Steen Pedersen; Søren Møller; Mette Juul Nielsen; Diana Julie Leeming; Morten Asser Karsdal; Holger Jon Møller; Flemming Bendtsen; Henning Grønbæk

doi:10.1371/journal.pone.0203200

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.

Affiliations

¹ Gastro Unit, Medical Division, Copenhagen University Hospital Amager Hvidovre, Hvidovre, Denmark.
² Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
³ Nordic Bioscience, Fibrosis Biology and Biomarkers, Herlev, Denmark.
⁴ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
⁵ Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

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 Receptor
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 Receptor
Mannose-Binding Lectins
Receptors, Cell Surface
Rifaximin

Grants and funding

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.