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Source at https://doi.org/10.1002/ehf2.12332. Licensed CC BY-NC-ND 4.0. Aims: Heart 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 results: GutHeart is a randomized, open‐label, controlled trial. Four centres will randomize 150 patients with stable HF and a left ventricular ejection fraction 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. Conclusions: This 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.