Alpha‐Ketoglutarate Attenuates Colitis in Mice by IncreasingLactobacillusAbundance and Regulating Stem Cell Proliferation via Wnt‐Hippo Signaling

Abstract

Scope: Inflammatory bowel disease is an inflammatory gastrointestinal disorder associated with intestinal barrier damage, cell proliferation disorder, and dysbiosis of the intestinal microbiota. It remains unknown whether alpha-ketoglutarate (𝜶-KG) can alleviate colitis in mice. Methods and results: Six-week-old male C57BL/6 mice supplemented with or without 0.5% 𝜶-KG (delivered in the form of sodium salt) are subjected to drinking water or 2.5% DSS to induce colitis. The results show that 𝜶-KG administration is attenuated the severity of colitis, as is indicated by reduced body-weight loss, colon shortening and colonic hyperplasia, and repressed proinflammatory cytokine secretion in DSS-challenged mice. Additionally, DSS-induced increases in malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2 ), and decreases in glutathione (GSH) levels are attenuated by 𝜶-KG administration. Further study shows that the protective effect of 𝜶-KG is associated with restoring gut barrier integrity by enhancing the expression of tight junction proteins, increasing Lactobacillus levels, and regulating gut hyperplasia by the Wnt-Hippo signaling pathway in DSS-induced colitis. Conclusion: Collectively, the data provided herein demonstrate that 𝜶-KG administration is attenuated mucosal inflammation, barrier dysfunction, and gut microflora dysbiosis. This beneficial effect is associated with increased Lactobacillus levels and regulated colon hyperplasia by the Wnt-Hippo signaling pathway.

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

“…Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease, which is associated with an increased risk of colorectal cancer (CRC) [ 55 ]. Compared with sporadic colorectal cancer (sCRC), IBD-related colorectal cancer (IBD-CRC) may represent a unique tumorigenesis pathway.…”

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

“…IBD, sclerosis, and arthritis are examples of autoimmune disorders brought on by dysregulation in T cells. 22 Patients with IBD had higher levels of IL-17A, which is generated by activated Th17 cells and induces NF-κB signaling. 22 However, it was noteworthy that α-KG supple- As the intestinal inflammation is accompanied by increased oxidative stress, we next analyzed the oxidative stress in our study.…”

“…22 Patients with IBD had higher levels of IL-17A, which is generated by activated Th17 cells and induces NF-κB signaling. 22 However, it was noteworthy that α-KG supple- As the intestinal inflammation is accompanied by increased oxidative stress, we next analyzed the oxidative stress in our study. As expected, we observed increased levels of MDA and H 2 O 2 in C. rodentium-infected mice, which were dampened by α-KG supplementation.…”

“…It is well-established that the differentiation of naive T cells results in T-cell subsets with an ability to prevent bacterial and fungal invasions. IBD, sclerosis, and arthritis are examples of autoimmune disorders brought on by dysregulation in T cells . Patients with IBD had higher levels of IL-17A, which is generated by activated Th17 cells and induces NF-κB signaling .…”

“…IBD, sclerosis, and arthritis are examples of autoimmune disorders brought on by dysregulation in T cells . Patients with IBD had higher levels of IL-17A, which is generated by activated Th17 cells and induces NF-κB signaling . However, it was noteworthy that α-KG supplementation abrogated the excessive activation of the proinflammatory response, which might block the vicious cycle of the cytokine storm.…”