Apolipoprotein E (apoE) is a 299 amino acid protein (34 kDa) involved in various biological processes, including a pivotal role in lipid metabolism and immunoinflammatory responses. Although much is known of apoE effects in the central nervous system, less is known regarding its role in the intestinal barrier function and mucosal immunology. ApoE has been recognized to influence intestinal barrier integrity and permeability, gut microbiota diversity, and gut inflammation and related dysbiosis, which the latter is frequently associated with inflammatory bowel disease (IBD). The proinflammatory microenvironment in the gut is also linked to dysbiosis and priming and activation of immune cells. The relationships among gut microbiota, apoE, and inflammation underscore the complex and intricate balance between gut health and illness states.