Rifaximin or Saccharomyces boulardii in heart failure with reduced ejection fraction: Results from the randomized GutHeart trial
Ayodeji Awoyemi,
Cristiane Mayerhofer,
Alex S Felix,
Johannes R Hov,
Samuel D Moscavitch,
Knut Tore Lappegård,
Anders Hovland,
Sigrun Halvorsen,
Bente Halvorsen,
Ida Gregersen,
Asbjørn Svardal,
Rolf K Berge,
Simen H Hansen,
Alexandra Götz,
Kristian Holm,
Pål Aukrust,
Sissel Åkra,
Ingebjørg Seljeflot,
Svein Solheim,
Andrea Lorenzo,
Lars Gullestad,
Marius Trøseid,
Kaspar Broch
Affiliations
Ayodeji Awoyemi
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway; Corresponding author at: Oslo University Hospital, Department of Cardiology, Ullevål., Kirkeveien 166, 0450 Oslo, Postboks 4956 Nydalen, 0424 Oslo, Norway.
Cristiane Mayerhofer
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Department of Cardiology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
Alex S Felix
Instituto Nacional de Cardiologia, 22240-006 Rio de Janeiro, Brazil
Johannes R Hov
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammation Medicine and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammation Medicine and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
Samuel D Moscavitch
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, 21040-900, Brazil
Knut Tore Lappegård
Division of Internal Medicine, Nordlandssykehuset, 8005 Bodø, Norway; Institute of Clinical Medicine, University of Tromsø, 9037 Tromsø, Norway
Anders Hovland
Division of Internal Medicine, Nordlandssykehuset, 8005 Bodø, Norway; Institute of Clinical Medicine, University of Tromsø, 9037 Tromsø, Norway
Sigrun Halvorsen
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway
Bente Halvorsen
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
Ida Gregersen
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
Asbjørn Svardal
Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
Rolf K Berge
Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
Simen H Hansen
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammation Medicine and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
Alexandra Götz
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammation Medicine and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
Kristian Holm
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammation Medicine and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
Pål Aukrust
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Section of Clinical Immunology and Infectious diseases, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway
Sissel Åkra
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway
Ingebjørg Seljeflot
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway
Svein Solheim
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway
Andrea Lorenzo
Instituto Nacional de Cardiologia, 22240-006 Rio de Janeiro, Brazil
Lars Gullestad
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Department of Cardiology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, 0450 Oslo, Norway
Marius Trøseid
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Section of Clinical Immunology and Infectious diseases, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway
Kaspar Broch
Department of Cardiology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, 0450 Oslo, Norway
Background: The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). Methods: In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF <40% and New York Heart Association functional class II or III, despite optimal medical therapy, to treatment (1:1:1) with the probiotic yeast Saccharomyces boulardii, the antibiotic rifaximin, or standard of care (SoC) only. The primary endpoint, the baseline-adjusted LVEF at three months, was assessed in an intention-to-treat analysis. Findings: We enrolled a total of 151 patients. After three months’ treatment, the LVEF did not differ significantly between the SoC arm and the rifaximin arm (mean difference was -1•2 percentage points; 95% CI -3•2 - 0•7; p=0•22) or between the SoC arm and the Saccharomyces boulardii arm (mean difference -0•2 percentage points; 95% CI -2•2 - 1•9; p=0•87). We observed no significant between-group differences in changes in microbiota diversity, TMAO, or C-reactive protein. Interpretation: Three months’ treatment with Saccharomyces boulardii or rifaximin on top of SoC had no significant effect on LVEF, microbiota diversity, or the measured biomarkers in our population with HF. Funding: The trial was funded by the Norwegian Association for Public Health, the Blix foundation, Stein Erik Hagen's Foundation for Clinical Heart Research, Ada og Hagbart Waages humanitære og veldedige stiftelse, Alfasigma, and Biocodex.
