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The chemical and physical barrier properties of the intestinal epithelium provide spatial separation of luminal contents and microbiota from the underlying immune system, which is a crucial feature in maintaining homeostasis. In IBD patients this homeostatic relationship is disturbed, characterized by a change in the microbiome, a breakdown of the epithelial barrier, and excessive inflammatory responses [2]. The epithelial monolayer is composed of functionally different intestinal epithelial cell (IEC) linages including enterocytes, goblet cells (GCs), enteroendocrine cells, Tuft cells, Paneth cells and M cells, all of which originate from epithelial stem cells located at the base of intestinal crypts [5]. In IBD, the abundance, activity and location of these cell types is altered [6, 7]. A wide range of antimicrobial peptides is secreted by GC and Paneth cells, helping to combat microbial colonization, and the expression of many of these peptides is regulated during inflammation [8]. In addition, studies in mice have shown that GCs are capable of sensing and delivering luminal content to underlying immune cells through goblet cell-associated antigen passages, a central process in the induction and maintenance of tolerance to harmless dietary antigens and commensal microbiota [9, 10]. In colonic IBD, both enteroendocrine cell numbers and activity are altered, with more serotonin+-cells in the mucosa [11, 12]. We and others have recently shown that epithelial serotonin reuptake is regulated in IBD, with reduced expression of the serotonin reuptake transporter (SERT), possibly resulting in increased levels of extracellular serotonin [13, 14]. The chronic inflammation in IBD is associated with an increased risk of colorectal cancer, particularly in UC, and successful treatment of IBD appears to reduce the colitis-associated colorectal cancer risk [15]. Key factors in the formation of colitis-associated colorectal cancer are the important immune regulators NFκB and Activator protein 1 (AP-1) components [16, 17]. As most new and emerging IBD treatments target pro-inflammatory regulators, it is a crucial balancing act to inhibit pathological inflammatory signaling, while retaining the antitumor immunity. Increased understanding of IEC signaling during inflammation can aid the selection of suitable targets for treatment. 2b1af7f3a8