Dihydroartemisinin Modulates Enteric Glial Cell Heterogeneity to Alleviate Colitis

Abstract The precise mechanism underlying the therapeutic effects of dihydroartemisinin (DHA) in alleviating colitis remains incompletely understood. A strong correlation existed between the elevation of glial fibrillary acidic protein (GFAP) + /S100 calcium binding protein B (S100β) + enteric glial cells (EGCs) in inflamed colonic tissues and the disruption of the intestinal epithelial barrier (IEB) and gut vascular barrier (GVB) observed in chronic colitis. DHA demonstrated efficacy in restoring the functionality of the dual gut barrier while concurrently attenuating intestinal inflammation. Mechanistically, DHA inhibited the transformation of GFAP + EGCs into GFAP + /S100β + EGCs while promoting the differentiation of GFAP + /S100β + EGCs back into GFAP + EGCs. Furthermore, DHA induced apoptosis in GFAP + /S100β + EGCs by inducing cell cycle arrest at the G0/G1 phase. The initial mechanism is further validated that DHA regulates EGC heterogeneity by improving dysbiosis in colitis. These findings underscore the multifaceted therapeutic potential of DHA in ameliorating colitis by improving dysbiosis, modulating EGC heterogeneity, and preserving gut barrier integrity, thus offering promising avenues for novel therapeutic strategies for inflammatory bowel diseases.