Inflammatory bowel disease: beyond the boundaries of the bowel

Abstract

Dysregulated inflammation in the gut, designated clinically as inflammatory bowel disease (IBD), is manifested by the prototypic phenotypes of an Arthus-like reaction restricted to the mucosa of the colon, as in ulcerative colitis, or a transmural granulomatous reaction, as in Crohn's disease, or an indeterminate form of the two polar types. That the inflammation of IBD can trespass the boundaries of the bowel has long been known, with articular, ophthalmologic, cutaneous, hepatobiliary or other complications/associations - some autoimmune and others not - affecting significant numbers of patients with IBD. Also notable is the frequency of diagnosis of IBD-type diseases on a background of systemic, (mostly myelo-hematological) disorders, associated with alterations of either (or both) innate or adaptive arms of the immune response. Finally, cases of IBD are reported to occur as an adverse effect of TNF inhibitors. Bone marrow transplant has been proven to be the only curative measure for some of the above cases. Thus, in effect, the IBDs should now be regarded as a systemic, rather than bowel-localized, disease. Genome-wide association studies have been informative in consolidating the view of three phenotypes of IBD (ulcerative colitis, Crohn's disease and mixed) and, notably, are revealing that the onset of IBD can be linked to polymorphisms in regulatory miRNAs, or to nucleotide sequences coding for regulatory lymphokines and/or their receptors. At the effector level, we emphasize the major role of the Th17/IL-23 axis in dictating the perpetuation of intestinal inflammation, augmented by a failure of physiological control by regulatory T-cells. In conclusion, there is a central genesis of the defects underlying IBD, which therefore, in our opinion, is best accommodated by the concept of IBD as more of a syndrome than an autonomous disease. This altered mindset should upgrade our knowledge of IBD, influence its medical care and provide a platform for further advances.

Advances in small bowel transplantation

“…Another possible mechanism can be donor lymphocytes having the genetic information for an abnormal inflammatory response. Further, in colonic mucosa, failure of physiological control by donor-derived regulatory T cells causes intestinal inflammation, which may demonstrate itself as an Arthus-like reaction (22). In a previous study, the use of anti-TNFα showed dramatic clinical and histological improvement in two children (23).…”

Inflammation: a highly conserved, Janus-like phenomenon—a gastroenterologist’ perspective

“…Rather, transitioning from rural to metropolitan life, switch from fresh prevalently vegetarian food to elaborated meat recipes, changes of feeding times due to work shift, may have shocked the microbiome, which did not keep pace with the rapid changes [76]. There is an extremely abundant literature summarizing the wealth of knowledge accumulated in a century of studies on IBD [77,78]; of an utmost interest is the report of recent epidemics-like IBD episodes in countries like Iran, where life and feeding habits have been partially Westernized [79]. A thorough scrutiny of these issues is provided in a recently published paper [80].…”

Circulating MicroRNAs as Biomarkers for Inflammatory Diseases

“…Given the important role of miRNAs in gene expression regulation, these small non-coding RNAs have been extensively evaluated for their role in IBD diagnosis. Furthermore, latest genome-wide association studies also supported the role of miRNAs in the development of IBD, since the onset of IBD can be linked to genetic polymorphisms in regulatory miRNAs [58]. …”