The gastrointestinal tract has long been hypothesized to function as “the motor” of multiple organ dysfunction syndrome. The gastrointestinal microenvironment is comprised of a single cell layer epithelia, a local immune system, and the microbiome. These three components of the intestine together play a crucial role in maintaining homeostasis during times of health. However, the gastrointestinal microenvironment is perturbed during sepsis, resulting in pathologic changes that drive both local and distant injury. In this review, we seek to characterize the relationship between the epithelium, gastrointestinal lymphocytes, and commensal bacteria during basal and pathologic conditions and how the intestinal microenvironment may be targeted for therapeutic gain in septic patients. •The epithelium, local immune system, and intestinal microbiome are interconnected and essential to maintaining host health.•Sepsis alters the intestinal microenvironment, promoting epithelial cell barrier breakdown, inflammation, and domination of pathogenic bacteria.•TPN and other modifications in nutrition affect epithelial integrity, immunological function, and bacterial pathogenesis.•Re-establishing a homeostatic intestinal microenvironment may be a useful treatment approach to sepsis.