Levels of primary BAs were reduced and specific secondary BAs increased in patients with chronic HF. This pattern was associated with reduced overall survival in univariate analysis, but not in multivariate analyses. Future studies should assess the regulation and potential role of BA metabolism in HF.

AimsHeart failure (HF) is a multifactorial disease. Current treatments target only a fraction of the putative pathophysiological pathways. In patients with HF, reduced cardiac output and congestion cause increased gut wall permeability. It has been suggested that leakage of microbial products is detrimental to the heart, at least partly through activation of systemic inflammatory pathways, which again could promote gut leakage. Whether manipulating the gut microbiota can improve cardiac function in patients with HF remains unknown. We aim to evaluate the effect of drugs targeting the gut microbiota on left ventricular function, quality of life, and functional capacity, as well as on markers of gut leakage and inflammation, in stable patients with HF with reduced ejection fraction.Methods and resultsGutHeart is a randomized, open‐label, controlled trial. Four centres will randomize 150 patients with stable HF and a left ventricular ejection fraction <40% to receive the antibiotic rifaximin, the probiotic yeast Saccharomyces boulardii (ATCC 74012), or no treatment (control) in a 1:1:1 fashion. Treatment will last for 3 months. The primary endpoint is baseline‐adjusted left ventricular ejection fraction as measured by echocardiography after 3 months. A further follow‐up 6 months after randomization will be undertaken.ConclusionsThis trial is likely to give new insights into important disease processes involving the gut microbiota in HF patients, hereby leading to new potential therapeutic strategies to prevent and down‐regulate the inflammation seen in these patients.

Background. Alterations in the partly microbiota-dependent carnitine-butyrobetaine (γBB)trimethylamine-N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection. Methods. We measured these metabolites in plasma from heart transplant recipients with everolimus (EVR)-based (n=32) and standard cyclosporine-based immunosuppression (n=30), at different time points and accompanied by assessment of CAV by intravascular ultrasound. Results. i) Baseline levels of carnitine, TMAO and TML were elevated in heart transplant recipients compared to controls, and TML remained elevated throughout the observation period, ii) The microbiota dependent metabolite γBB increased steadily during three years follow-up, with a similar decrease in its endogenous precursor TML, iii) The increase in γBB and change in TML was associated with change in total atheroma volume from baseline to three years, iv) Increase in γBB and carnitine levels from baseline to 1 year was associated with increased frequency of acute rejection within the first year after heart transplant. Conclusion. Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during three years follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs and the gut microbiota could influence acute rejection and CAV development, in order to delineate mechanisms and potential novel treatment targets.