The role of genetic alterations in the gut-joint axis of Crohn's disease and Spondyloarthropathies

Next to the known clinical and immunological links between CD and SpA, we demonstrate in this work a genetic connection between these two disorders. Carriership of CD-related CARD15 polymorphisms in SpA patients is associated with the presence of chonic gut inflammation, similar to CD. Whether these genetic variants in CD and SpA play a direct role in the origin of inflammation at distance of the gut, is uncertain. The frequent association between axial involvement, peripheral arthritis and uveitis in CD, suggests however common etiological factors underlying these different extraintestinal manifestations. In view of the multigenic character of CD and SpA, presumably several genes play a role in the disturbed handling of bacterial flora and the possible circulation of antigens between intestine and joint. Further research in both disease entities is mandatory to investigate how bacterial components are transported to extraintestinal organs. Functional study of isolated monocytes of CD patients demonstrated for the first time a disturbed immunological response in single heterozygous carriers of CARD15 polymorphisms, representing the largest group of mutation carriers. Monocytes of these patients showed an aberrant early cytokine secretion after infection with AIEC, a bacterial strain specifically associated with CD. Moreover, these polymorphisms also seem to induce a disturbed humoral response, reflected by the association with anti-Saccharomyces cerevisiae antibodies. We also confirmed the link between CD and SpA at the transcriptome level. Remarkable similarities were noted in the genetic expression profile of non-inflammatory colonic biopsies of CD patients and SpA patients with chronic intestinal inflammation using array analyses. Finally, we demonstrated that the search for differential gene expression may lead to the identification of new disease-modifying genes. Metallothioneins are substantially down-regulated in CD patients with colonic involvement. Furthermore, we identified a polymorphism in MTF1, a gene for the main transcriptional regulator for MT, which also was related with disease location in CD. In conclusion, this work provides new proof for the close (etiopatho)genetic relationship between CD and SpA, presents new insights in the functional role of CD-associated CARD15 polymorphisms and describes an alternative approach (via differential gene expression) to identify new potential susceptibility or disease-modifying genes.