Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease

Abstract

Compromised intestinal barrier function is a prominent feature of inflammatory bowel disease (IBD). However, links between intestinal barrier loss and disease extend much further, including documented associations with celiac disease, type I diabetes, rheumatoid arthritis, and multiple sclerosis. Intestinal barrier loss has also been proposed to have a critical role in the pathogenesis of graft-versus-host disease (GVHD), a serious, potentially fatal consequence of hematopoietic stem cell transplantation. Experimental evidence has begun to support this view, as barrier loss and its role in initiating and establishing a pathogenic inflammatory cycle in GVHD is emerging. Here we discuss similarities between IBD and GVHD, mechanisms of intestinal barrier loss in these diseases, and the crosstalk between barrier loss and the immune system, with a special focus on natural killer (NK) cells. Unanswered questions and future research directions on the topic are discussed along with implications for treatment.

Effects of protein malnutrition on tolerance to helminth infection

“…Moreover, permeability to macromolecules may initiate inflammatory responses because of leakage of microbial or food antigens. For instance, in humans, increased intestinal permeability is thought to be a cause of the inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis [18]. Thus, maintaining intestinal barrier function despite high worm loads is clearly a potentially important aspect of tolerance to helminth infection.…”

“…a measure of health or infection-induced damage) against parasite load, where a steeper slope means lower tolerance [15]. We measured the effect of infection on host health/fitness in two ways: (i) relative weight change during the experiment, (ii) intestinal permeability to macromolecules (as an indication of tissue damage at the site of infection [16]; increased permeability impairs nutrient absorption and can lead to inflammatory disease [17,18]). Our aim was to test if nutritional status affected the slope of the relationship between each of these health measures and parasite load.…”

The mucosal barrier at a glance

“…As a result, barrier loss can be detected as increased flux across the pore pathway, the leak pathway or the unrestricted pathway. The latter is a tight-junction-independent potential pathway that becomes functional in disease owing to direct epithelial damage (Nalle and Turner, 2015). The unrestricted pathway allows large quantities of large and small molecules, including microbes, to cross the damaged epithelial barrier (Aihara et al, 2016;Yu et al, 2016).…”

Intravenous mesenchymal stromal cell therapy for inflammatory bowel disease: Lessons from the acute graft versus host disease experience

“…Administration of corticosteroids is standard first-line therapy for acute GVHD but leads to remission in less than half of patients. Second-line therapy is variable, depending on the experience of the clinician and availability of therapies [4][5][6]. Anti-thymocyte globulin, pentostatin, mycophenolate mofetil and other monoclonal antibodies (e.g., rituximab, etanercept) have been used to treat steroid-refractory GvHD [7][8][9][10][11].…”