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Sepsis is a leading cause of death in critically ill patients, primarily due to multiple organ failures. It is associated with a systemic inflammatory response that plays a role in the pathogenesis of the disease. Intestinal barrier dysfunction and bacterial translocation (BT) play pivotal roles in the pathogenesis of sepsis and associated organ failure. In this review, we describe recent advances in understanding the mechanisms by which the gut microbiome and BT contribute to the pathogenesis of sepsis. We also discuss several potential treatment modalities that target the microbiome as therapeutic tools for patients with sepsis.