α-Ketoglutarate Restores Intestinal Barrier Function through Promoting Intestinal Stem Cells-Mediated Epithelial Regeneration in Colitis

This study investigated the preventive effects of alpha-ketoglutarate (alpha-KG, in the form of sodium salt) on a Citrobacter rodentium (CR)-induced colitis and explored potential mechanisms. The results demonstrated that CR caused body weight loss and colon length shortening, which were abrogated by the alpha-KG administration. The colon length of mice in the alpha-KG plus CR group was significantly higher than that of mice in the CR group (6.9 +/- 0.59 (mean +/- SD) vs 6.1 +/- 0.55; P < 0.05). This beneficial effect was associated with regulating endoplasmic reticulum (ER) stress signaling. In addition, small intestinal organoids generated from intestinal crypts of mice were exposed to alpha-KG in the presence of TNF-alpha or IWR-1 to assess stem cell activity in vitro. The results demonstrated that TNF-alpha exposure decreased the viability of organoids and impaired barrier function by suppressing Wnt signaling, which was abolished by alpha-KG. Interestingly, the protective effect of alpha-KG on intestinal barrier function was abrogated by the inhibitor of Wnt signaling in the intestinal organoids. Taken together, alpha-KG restored barrier function by regulating ER stress and activating Wnt/beta-catenin-medicated intestinal stem cell proliferation and differentiation.

Automated summary

This study found that alpha-ketoglutarate (alpha-KG) has preventive effects on Citrobacter rodentium-induced colitis by regulating endoplasmic reticulum stress and activating Wnt signaling to restore barrier function.