Inflammatory bowel disease: An archetype disorder of outer environment sensor systems

Abstract

The pathogenesis of the two inflammatory bowel disease (IBD) phenotypes ulcerative colitis (UC) and Crohn’s disease (CD) has remained elusive, thus frustrating attempts at defining a cure. IBD often presents as a complex inflammatory process wherein colon lesions (UC) or widespread ulceration and fissure (CD) might be accompanied by ancillary extra-intestinal manifestations involving the eye, skin, joints or liver, but also by full-blown “autoimmune” disorders from psoriasis and multiple sclerosis to rheumatoid arthritis; attempts at unraveling a link or a hierarchical order in these entities have proven almost fruitless. More recently, the input of genetics has suggested that the IBDs might be multi-organ inflammatory processes, elicited by a large number of low-penetrance susceptibility genes, with environmental factors needed to induce full-blown disease. At a noteworthy exception to this rule, the description of the nucleotide-oligomerization domain (NOD) gene mutations in CD came at the beginning of the 2000s: the NOD-LRR are part of a highly conserved microbial sensor system which respond to bacterial peptidoglycans by mounting an inflammatory response. At least in Caucasian patients, the prevalently loss-of-function mutation of NOD permitted to unexpectedly define CD as an immune deficiency state, and upon its recent description in apparently unrelated disorders such as the Blau syndrome (a granulomatous pediatric syndrome), and perhaps in psoriasis and chronic obstructive pulmonary disorders, has contributed to revolutionize our view of IBD and CD in particular. The latter affection, together with psoriasis and chronic pulmonary disease can now be included into a newly identified category named “barrier organ disease”, wherein a barrier organ is defined as a large mucosal or epithelial surface with an abundant metagenomic microbial population and an underneath reactive tissue, the whole structure being in contact with the outer environment and capable to react to it. Personalized treatments and empowerment of research across different disease phenotypes should be the advantages of this novel mindset.

Keywords: Inflammatory bowel disease, Psoriasis, Chronic pulmonary disease, Innate immunity, Nucleotide oligomerization domains

Core tip: With its extended mucosal surface in contact with the environment, an overly reactive lymphoid tissue underneath, and an extraordinarily abundant metagenomic flora, the gut is in the position to play a central role in the pathogenesis of both its core disorders (inflammatory bowel disease) and remote autoinflammatory or immunopathic diseases. The IBDs have been listed as a “barrier organ dysfunction”. We hereby focus on psoriasis, a barrier organ dysfunction which is often co-morbid with IBD, sharing with it microbial receptor genetic polymorphisms, and response to therapy. This comprehensive mindset shall boost science and drive our medical choices for immunoinflammatory pathology.