Figure 4.

Role of epithelial cell integrity and mucus production in gut health and disease. Proteins regulating cell structure (e.g., DLG5) or metabolic functions (e.g., XBP1) maintain IEC integrity. IECs in constant contact with luminal toxins and xenobiotics dispose of these harmful molecules by means of several transporter proteins, such as MDR1, OCTN1, and 2. IECs secrete a thick layer of mucus, whose production is finely regulated by different proteins, including MUC family members and POFUT1. Loss of control over ER stress, resulting from XBP1 dysfunction and accumulation of toxic molecules inside IECs, secondary to transporter molecule loss of function, cause IEC damage, defective defensin secretion from Paneth cells, and release of proinflammatory mediators leading to immune activation. Direct exposure of IEC to luminal toxins/antigens is increased by deletion of MUC2, 3, and 4, which leads to dramatic reduction of mucus production, and eventually to intestinal inflammation. Conversely, overproduction of mucus is also harmful, leading to bacterial overgrowth in intestinal crypts, as seen in POFUT1 deficiency, causing a dysregulation of the epithelial transcription factor, NOTCH that controls IEC proliferation and differentiation.