Heart failure is a common medical problem and continuous-flow left ventricular assist devices (LVADs) are a mainstay of advanced heart failure therapy. However, non-surgical bleeding (bleeding at a non-operative site) complicates the post-LVAD course in up to 30% of patients, restricting the more widespread use of LVADs. While most LVAD-related non-surgical bleeding occurs in the setting of new angiodysplasia in the gastrointestinal tract, the molecular mechanisms leading to angiodysplasia in LVAD patients are presently unknown. In this series of experiments, we demonstrate that high levels of Angiopoietin-2 (Ang-2) and Tumor Necrosis Factor-α (TNF-α) in LVAD patients lead to altered blood vessel formation and are strongly associated with bleeding events. These bleeding events are associated with gastrointestinal dysbiosis and low levels of butyrate, a known suppressor or Ang-2 and TNF-α. Our findings suggest that inhibition of Ang-2 and TNF-α with oral butyrate supplementation might be a possible treatment for LVAD-related bleeding.