Fatty acid receptors as new players in Colorectal Cancer: implication for new therapeutic strategies

Crohn’s Disease (CD) and Ulcerative Colitis (UC), which affect about 2 million people in the USA and Europe1, belong to a class of chronic inflammatory disorders of the gastrointestinal tract known as Inflammatory Bowel Disease (IBD), whose etiogenesis is still unknown. Clinically, in CD the inflammation is discontinuous and may interest any part of the gut, but most frequently it is found in the terminal ileum and colon (Figure 1A). Differently from CD, in UC inflammation is continuous and restricted to the large intestine, although there may be an involvement of the terminal ileum (Figure1B). Histologically, CD is featured by transmural inflammation of the gut wall, with granuloma formation, whereas UC inflammation interests only gut mucosa and submucosa. UC and CD share common symptoms, that include diarrhea (with or without blood), fever and weight loss. The gut mucosa hosts several cellular and molecular components that coexist with a refined equilibrium, and respond to external triggers to maintain the mucosal homeostasis. Therefore, activities of these gut residents need to be finely modulated and constantly balanced, in order to avoid chronicity of inflammation and tissue damage2. Alterations of such an equilibrium are associated with IBD pathogenesis. In fact, IBD is characterized by dysregulation of various cellular and non-cellular components, that all together may lead to ulceration of the epithelial barrier3. As a consequence, the epithelial barrier damage allows commensal bacteria and microbial products to translocate into and colonize the intestinal mucosa, triggering the release of a plethora of pro-inflammatory stimuli which can activate an uncontrolled immune response that fails to be resolved, and leads to chronic inflammation4,5. Both immune and non-immune components of the intestinal mucosa have been shown to exert a keyrole in IBD pathogenes is. For example, innate immune cells (e.g., neutrophils, monocytes, and macrophages) hold the capability to remodel T cell responses during the inflammatory process3. On the other side, the non-immune compartment has also been shown to play a role in IBD development and progression6. For example, epithelial cell dysfunctions, including mucosal barrier ulceration and defective mucus production are considered promoters of intestinal inflammation; this is due to their central role as first line of gut defense against bacteria and other microorganisms6. Besides, defects in the biological activities of stromal and endothelial cells are also involved in IBD pathogenesis; in fact, while stromal cells hold immune-modulatory actions and the capability to clear chemokines and cytokines from the inflammatory milieu, endothelial cells are crucial not only for the angiogenic process, but also for the regulation of leukocyte adhesion, and trafficking across the hematic and lymphatic barriers6. The gastrointestinal tract hosts the largest microbial community of the organism that can be shaped from the childhood to the adult age by dietary habits, environmental and genetic factors7,8. While in healthy conditions, there is an equilibrium between the gut microbiome, the mucosal barrier, and the immune system, in IBD this equilibrium is compromised, leading to intestinal “dysbiosis”9 (Figure 2). However, whether intestinal dysbiosis is the cause or the consequence of IBD is still under investigation. Gut mucosal barriers, which are classified into chemical, including antimicrobial peptides (AMPs), and physical barriers (mucus layer and cell junctions), own the ability to sense dysbiosis and to protect the intestine from invading microorganisms. These barriers avoid unnecessary immune responses to gut commensal microbes, but when they succeed to invade the gut mucosa, intestinal inflammation occurs10.