This study investigated the preventive effects of α-ketoglutarate
(α-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 α-KG administration.
The colon length of mice in the α-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 α-KG in the presence
of TNF-α or IWR-1 to assess stem cell activity in vitro. The results demonstrated that TNF-α exposure decreased the
viability of organoids and impaired barrier function by suppressing
Wnt signaling, which was abolished by α-KG. Interestingly, the
protective effect of α-KG on intestinal barrier function was
abrogated by the inhibitor of Wnt signaling in the intestinal organoids.
Taken together, α-KG restored barrier function by regulating
ER stress and activating Wnt/β-catenin-medicated intestinal
stem cell proliferation and differentiation.
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