Mesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory disorders, including Crohn's disease. MSCs are pluripotent cells with immunosuppressive properties. Recent data suggest that resting MSCs do not have significant immunomodulatory activity, but that the immunosuppressive function of MSCs has to be elicited by interferon-γ (IFN-γ). In this article, we assessed the effects of IFN-γ prestimulation of MSCs (IMSCs) on their immunosuppressive properties in vitro and in vivo. To this end, we pretreated MSCs with IFN-γ and assessed their therapeutic effects in dextran sodium sulfate (DSS)- and trinitrobenzene sulfonate (TNBS)-induced colitis in mice. We found that mice treated with IMSCs (but not MSCs) showed a significantly attenuated development of DSS-induced colitis. Furthermore, IMSCs alleviated symptoms of TNBS-induced colitis. IMSC-treated mice displayed an increase in body weight, lower colitis scores, and better survival rates compared with untreated mice. In addition, serum amyloid A protein levels and local proinflammatory cytokine levels in colonic tissues were significantly suppressed after administration of IMSC. We also observed that IMSCs showed greater migration potential than unstimulated MSCs to sites within the inflamed intestine. In conclusion, we show that prestimulation of MSCs with IFN-γ enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis. These data demonstrate that IFN-γ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo.

Patients frequently wonder whether their dietary pattern influences the course of inflammatory bowel disease (IBD). Many patients even avoid certain foods that aggravate their symptoms. Although interest in nutritional interventions is rising among physicians, the current application of nutritional interventions in the IBD population is limited due to the lack of scientific evidence from clinical trials. Several studies, however, have identified associations between diet, gut microbiota, intestinal epithelial integrity, and mucosal immune responses. In patients consuming predominantly a Western diet high in n-6 poly-unsaturated fatty acids (PUFAs), sugars, and meat, and low in fruits and vegetables, an impaired gut epithelial barrier and disturbances in the intestinal microbiota have been observed, resulting in a chronic mucosal inflammation. An anti-inflammatory diet may restore this disbalance. In this review, we discuss the effects of diet on the composition of the microbiota, the gut epithelial barrier function, and the mucosal immune system.

Background: Local administration of mesenchymal stromal cells (MSCs) into the fistula tract seems to improve patient outcome in perianal fistulas due to Crohn’s disease (CD). In this paper we propose a standardized and validated protocol for the local administration of MSCs for CD perianal fistulas to be able to reliably assess efficacy. Materials and methods: A working group consisting of gastroenterologists and surgeons with expertise in the treatment of perianal CD developed a consensus perianal fistula treatment protocol for local MSC treatment of perianal fistulizing CD. The treatment protocol was validated during a trial of allogeneic bone marrow-derived MSCs for the treatment of refractory perianal Crohn’s fistulas. Results: Localization and classification of perianal fistulas with MRI and rectoscopy is of crucial importance prior to surgical intervention with local therapy administration. Examination under anesthesia is necessary to incise and drain abscesses when present. Optimization of medical treatment when active luminal CD is present, is the first step before embarking on surgery and local therapy administration. In addition, strictures preventing the surgeon from adequately performing the surgical procedure have to be endoscopically dilated. Curettage of the fistula tract has an important role as long-standing CD perianal fistulas close poorly without removal of their epithelial lining. To diminish bacterial contamination of the fistula, the internal opening has to be closed. The origin of the fistula is the internal opening, therefore, efficacy of MSCs is presumably the highest when they are injected into the tissue around the internal opening. Conclusion: In this article, we propose a standardized method of local MSC administration for perianal fistulizing CD. The use of this standardized and validated protocol for the administration of local treatment of CD perianal fistulas will allow reliable comparison of the efficacy of local therapies in future.

Mesenchymal stromal cell [MSC] therapy is a new treatment for perianal fistulas in Crohn's disease. Although MSC therapy shows a favourable safety profile, long-term safety data are limited. We detected an Epstein Barr virus [EBV]-associated B cell lymphoproliferative lesion in the rectum of a patient 4 years after local administration of MSCs for his perianal fistulas. To investigate whether MSC therapy contributed to the development of this lymphoproliferative disease, we analyzed the possibility of EBV transfer via the MSC product and the persistence of MSCs in the lymphoproliferative lesion using short tandem repeat analysis.