Thromb Haemost 2022; 122(04): 540-551
DOI: 10.1055/s-0041-1733906
Blood Cells, Inflammation and Infection

Impact of a Vancomycin-Induced Shift of the Gut Microbiome in a Gram-Negative Direction on Plasma Factor VIII:C Levels: Results from a Randomized Controlled Trial

Gro Grimnes
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
2   Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
,
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
3   Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Kristian Hindberg
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
,
Mark Davids
4   Department of Vascular Medicine, Amsterdam University Medical Centers—location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Max Nieuwdorp
4   Department of Vascular Medicine, Amsterdam University Medical Centers—location AMC, University of Amsterdam, Amsterdam, The Netherlands
5   Department of Internal Medicine, Diabetes Center, Amsterdam University Medical Centers—location VUmc, Amsterdam, The Netherlands
6   Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
,
Tom E. Mollnes
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
7   Research Laboratory, Nordland Hospital, Bodø, Norway
8   Department of Immunology, Oslo University Hospital and K.G. Jebsen IRC, University of Oslo, Oslo, Norway
,
Annika E. Michelsen
9   Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
10   Faculty of Medicine, University of Oslo, Oslo, Norway
,
Thor Ueland
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
9   Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
10   Faculty of Medicine, University of Oslo, Oslo, Norway
,
Sigrid K. Brækkan
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
2   Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
,
John-Bjarne Hansen
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
2   Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
,
Vladimir Tichelaar
1   Department of Clinical Medicine, K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT—The Arctic University of Norway, Tromsø, Norway
3   Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
11   Certe Thrombosis Service, Groningen, The Netherlands
› Author Affiliations
Funding G.G. is in receipt of an independent grant from the North Norwegian Health Authorities. V.T. is in receipt of an independent grant (Mandema Stipendium) from University Medical Center Groningen, University of Groningen, the Netherlands. M.N. is supported by a ZONMW-VIDI grant 2013 (016.146.327) and CVON Young Talent grant 2012, and supported by Le Ducq consortium grant 17CVD01 and Novo Nordisk Foundation. The laboratory analyses were financially supported to T.E.M. by The Norwegian Council on Cardiovascular Disease and The Odd Fellow Foundation.

Abstract

Background Inflammation is present in several conditions associated with risk of venous thromboembolism. The gut microbiome might be a source of systemic inflammation and activation of coagulation, by translocation of lipopolysaccharides from gram-negative bacteria to the systemic circulation.

Objective To investigate whether a vancomycin-induced shift of the gut microbiome in a gram-negative direction influences systemic inflammation and plasma factor (F) VIII procoagulant activity (FVIII:C).

Methods and Results We performed a randomized controlled trial including 43 healthy volunteers aged 19 to 37 years. Twenty-one were randomized to 7 days of oral vancomycin intake and 22 served as controls. Feces and blood were sampled at baseline, the day after the end of intervention, and 3 weeks after intervention. Gut microbiome composition was assessed by amplicon sequencing. FVIII:C was measured using an activated partial thromboplastin time-based assay, cytokines were measured using multiplex technology, complement activation was measured using the enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay. Vancomycin intake reduced gut microbiome diversity and increased the abundance of gram-negative bacteria. Change in FVIII:C in the intervention group was +4 IU/dL versus −6 IU/dL (p = 0.01) in the control group. A similar change was observed for log-transformed CRP (+0.21 mg/dL vs. −0.25 mg/dL, p = 0.04). The cytokines and complement activation markers remained similar in the two groups.

Conclusion The found slight increases in FVIII:C and CRP levels might support the hypothesis that a vancomycin-induced gram-negative shift in the gut microbiome could induce increased systemic inflammation and thereby a procoagulant state.

Author Contributions

G.G. and V.T. conceived the idea of the study. V.T. and J-.B.H. obtained funding for the study. G.G., V.T., and J-.B.H. designed the study. G.G. and V.T. wrote the protocol and obtained approval of the Regional Ethics Committee and the Clinical Research Unit at the University Hospital of North Norway. G.G. ran the trial as the principal investigator, included the volunteers, and collected the data. G.G. and K.H. performed statistical analysis on the inflammatory and coagulation outcomes. M.D. and M.N. performed statistical analysis of the microbiome data. M.D., M.N., V.T., S.B., and G.G. interpreted the results of the microbiome data. A.E.M. and T.U. performed the zonulin assays. T.E.M. analyzed the cytokines and complement activation products and interpreted the data. G.G., V.T., S.B., K.H., J-.B.H., and S.K.B. interpreted all results of all outcomes in the light of the hypothesis of the study. G.G. and S.B. drafted the manuscript with supervision of V.T., J-.B.H., and S.K.B. K.H., T.E.M., M.D., A.E.M., T.U., M.N., and S.K.B. critically reviewed the manuscript.




Publication History

Received: 02 March 2021

Accepted: 01 July 2021

Article published online:
24 August 2021

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