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

Abstract

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.

α-Ketoglutarate for Preventing and Managing Intestinal Epithelial Dysfunction

“…DSS-treated mice provided with 1.0% AKG loss less weight than their counterparts [ 66 ]. Citrobacter rodentium -induced colitis mice receiving 0.5% AKG in their drinking water ameliorated colon shortening and tight junction protein suppression [ 67 ]. TNFα, interferon-γ, and proinflammatory IL concentrations in serum were also decreased [ 67 ].…”

“…Citrobacter rodentium -induced colitis mice receiving 0.5% AKG in their drinking water ameliorated colon shortening and tight junction protein suppression [ 67 ]. TNFα, interferon-γ, and proinflammatory IL concentrations in serum were also decreased [ 67 ]. In DSS/azoxymethane mice, 1.0% AKG supplementation reduced inflammatory index and tumor number, associated with decreased concentrations of IL-6, IL-22, IL-1b, and TNFα [ 68 ].…”

“…Additionally, staining of colonic tissue for the membrane protein F4/80, a pan macrophage marker, revealed lower macrophage infiltration in the mice that received AKG [ 66 ]. Similarly, supplementation with 0.5% AKG ameliorated macrophage infiltration in the colon of mice challenged with C. rodentium, as demonstrated by reduced F4/80 + and CD11b + staining [ 67 ]. Furthermore, 0.5% AKG in drinking water decreased concentrations of CD11b + CD64b + macrophages in the spleen of mice subjected to DSS-induced colitis [ 65 ].…”

“…AKG demonstrates the ability to alleviate oxidative stress in different animal models, leading to the restoration of vital antioxidant enzymes ( Table 1 ) [ 65 , 67 , 70 , 92 , 94 ]. For instance, in a mouse model of C. rodentium -induced colitis, the provision of 0.5% AKG in drinking water reduced serum concentrations of malondialdehyde and hydrogen peroxide [ 67 ].…”

“…AKG demonstrates the ability to alleviate oxidative stress in different animal models, leading to the restoration of vital antioxidant enzymes ( Table 1 ) [ 65 , 67 , 70 , 92 , 94 ]. For instance, in a mouse model of C. rodentium -induced colitis, the provision of 0.5% AKG in drinking water reduced serum concentrations of malondialdehyde and hydrogen peroxide [ 67 ]. Exposure to C. rodentium decreased mRNA amounts of glutathione synthetase, N rf 2 , and its downstream target, NAD(P)H dehydrogenase quinone 1, in the colon, all of which were restored by AKG [ 67 ].…”