Microbes play an important role in human health and disease. In the setting of heart failure (HF), substantial hemodynamic changes such as hypoperfusion and congestion in the intestines can alter gut morphology, permeability, function, and possibly the growth and composition of gut microbiota. These changes can disrupt the barrier function of the intestines, and exacerbate systemic inflammation through microbial or endotoxin translocation into systemic circulation. Furthermore, cardio-renal alterations via metabolites derived from gut microbiota can potentially mediate or modulate HF pathophysiology. Recently, trimethylamine N-oxide (TMAO) has emerged as a key mediator which provides mechanistic link between gut microbiota and multiple cardiovascular diseases, including HF. Potential intervention strategies which may target this microbiota-driven pathology include dietary modification, prebiotics or probiotics, and selective binders of microbial enzymes or molecules - yet further investigations into their safety and efficacy are warranted.