Immunosuppressive therapy of immune-mediated GI damage may impair epithelial regeneration

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Abstract Glucocorticoids (GC) are a standard therapy of immune-mediated gastrointestinal (GI) damage. However, there is little understanding of the effects that GC use may have on intestinal epithelium and its regenerative function. Using ex vivo organoid models of immune-mediated intestinal injury, we sought to investigate direct effects of GC on intestinal epithelium and test the impact of GC on cytokine- and T-cell-mediated effects. GC suppressed proliferation of small intestine (SI) organoids, reducing organoid size and decreasing cell cycle progression of Lgr5+ intestinal stem cells. Consistently, GC treatment of C57BL/6J mice suppressed epithelial proliferation, decreasing crypt height and reducing the percentage of Ki67+ crypt cells in vivo. We next investigated the role of GC-mediated epithelial suppression in the setting of tissue damage, modeling immune-mediated GI pathology by culturing organoids in the presence of IFNγ and by co-culturing organoids with allogeneic T-cells. Culture with GC in addition to IFNγ significantly increased the toxicity of IFNγ leading to reduced efficiency of organoid formation. Consistently, GC pretreated organoids were more susceptible to allogeneic T-cells with reduced formation efficiency. Finally, we studied cytokine-mediated epithelial regeneration in the context of GC treatment. Culturing organoids with both GC and IL-22 indicated that IL-22 could promote regeneration of intestinal epithelium in the presence of GC. Taken together, our findings indicate that GC, which are necessary clinically for suppressing pathologic inflammatory immune responses, may have direct effects on the epithelium potentially impairing protective regeneration responses and augmenting toxicity.