The glucocorticoid budesonide has protective and deleterious effects in experimental colitis in mice

Abstract

Glucocorticoids are widely used for the management of inflammatory bowel disease, albeit with known limitations for long-term use and relevant adverse effects. In turn, they have harmful effects in experimental colitis. We aimed to explore the mechanism and possible implications of this phenomenon. Regular and microbiota depleted C57BL/6 mice were exposed to dextran sulfate sodium (DSS) to induce colitis and treated with budesonide. Colonic inflammation and animal status were compared. In vitro epithelial models of wound healing were used to confirm the effects of glucocorticoids. Budesonide was also tested in lymphocyte transfer colitis. Budesonide (1–60 μg/day) exerted substantial colonic antiinflammatory effects in DSS colitis. At the same time, it aggravated body weight loss, increased rectal bleeding, and induced general deterioration of animal status, bacterial translocation and endotoxemia. As a result, there was an associated increase in parameters of sepsis, such as plasma NO_x, IL-1β, IL-6, lung myeloperoxidase and iNOS, as well as significant hypothermia. Budesonide also enhanced DSS induced colonic damage in microbiota depleted mice. These effects were correlated with antiproliferative effects at the epithelial level, which are expected to impair wound healing. In contrast, budesonide had significant but greatly diminished deleterious effects in noncolitic mice or in mice with lymphocyte transfer colitis. We conclude that budesonide weakens mucosal barrier function by interfering with epithelial dynamics and dampening the immune response in the context of significant mucosal injury, causing sepsis. This may be a contributing factor, at least in part, limiting clinical usefulness of corticoids in inflammatory bowel disease.

Introduction

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a multifactorial disorder characterized by chronic recurrent inflammation of the gastrointestinal tract. The molecular pathogenesis of IBD has not been fully elucidated, although an exacerbated mucosal immune response triggered by bacteria present in the intestinal flora in genetically susceptible individuals appears to be a plausible mechanism. To date, it remains unclear whether a breakdown of the immune tolerance is the primary cause of these diseases or if the inflammation arises downstream of an initial defect of the intestinal barrier function [1].

Glucocorticoids (GCs) are the therapy of choice for the treatment of IBD bouts [2]. Upon GC binding, the glucocorticoid receptor modulates gene expression by at least two mechanisms: by binding to specific response elements in DNA, and by interference with other transcription factors [3]. The latter appears to play a dominant role in the immunosuppressive effects of GCs [4]. However, some of the anti-inflammatory effects of these molecules depend, at least in part, on the transactivation-induced expression of several proteins like glucocorticoid-induced leucine zipper (GILZ) and mitogen activated protein kinase (MAPK) phosphatase (MKP-1) [5], [6]. Despite their clinical efficacy in IBD, GCs have significant limitations. The response is fairly heterogeneous, with only about 40–50% of IBD patients responding adequately to therapy. Around 20% are nonresponders and the remaining 30% become GC-dependent [7]. Furthermore, GCs are characterized by severe and life-threatening side effects that significantly reduce the duration of its clinical use since they appear in over 50% of patients. In addition, the fact that GCs are not useful to prolong remission [8], together with the limitations cited above, justifies the application of alternative therapeutic tools, such as immunosuppressive drugs or anti-TNFα biologicals, and current research is directed to finding new drugs with a better efficacy/risk profile.

GCs have been used as reference antiinflammatory treatments in animal models of IBD, with the expected benefit in terms of intestinal antiinflammatory activity. However, we and other authors have observed worsening in the animal general condition and even increased mortality in GC treated animals with experimental colitis, namely trinitrobenzenesulfonic acid (TNBS) and dextran sulfate sodium (DSS) colitis [9], [10], [11], [12], [13]. We undertook the present study to clarify the mechanism of GC deleterious effects in experimental colitis, and ultimately to anticipate whether they may be relevant for IBD management. Our data indicate that GCs weaken mucosal barrier function in the context of intestinal inflammation and/or injury, and suggest that this may play a role clinically by limiting their efficacy and usefulness in IBD patients.