The intestinal epithelium acts as the first line of defence against pathogens present in the lumen of the gastrointestinal tract. The epithelium is composed of a single monolayer that includes a variety of cell types, each of which play roles in nutrient and water absorption, antimicrobial defence, and immunomodulation to maintain a homeostatic gut environment. Tight junction (TJ) complexes between adjacent intestinal epithelial cells are responsible for the structural integrity of the gut barrier and controlling the paracellular translocation of luminal contents. The effectiveness of TJs can be impacted by both genetic and environmental factors including microbiota dysbiosis and dietary components. The increased systemic entry of luminal contents has been associated with the development, progression, and/or relapse of autoimmune diseases such as Crohn’s and rheumatoid arthritis. In particular, the extraintestinal spread of luminal microbes possessing components with structural similarity to those of the human host are thought to be involved in the breakdown of immune tolerance towards host components. Here, the structure and function of the intestinal epithelium are discussed as well as the genetic and environmental factors that influence its permeability. There is emphasis on the role of increased intestinal permeability and how the subsequent translocation of luminal contents could be involved in the development and/or exacerbation of autoimmune diseases. This review reinforces how protecting the integrity of the intestinal epithelium and minimising immunological exposure to luminal components, either directly or indirectly, could be a useful strategy in reducing the prevalence and severity of autoimmune diseases.