Alpha-Ketoglutarate Attenuates Colitis in Mice by Increasing <i>Lactobacillus</i> Levels and Regulating Stem Cell Proliferation via Wnt-Hippo Signaling

Background: 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: Six-week-old male C57BL/6 mice supplemented with or without 0.5% (w/w) α-KG (delivered in the form of a sodium salt) were subjected to drinking water or 2.5% DSS to induce colitis. Histological damage, inflammatory cell infiltration, and the colonic microbiome community were analyzed to evaluate the beneficial effect of α-KG administration.Findings: Alpha-KG administration attenuated the severity of colitis, as indicated by reduced body weight loss, reduced colon shortening, decreased myeloperoxidase (MPO) activity, repressed proinflammatory cytokine secretion, and decreased histological damage in DSS-challenged mice. Additionally, DSS-induced increases in malondialdehyde (MDA) and hydrogen peroxide (H2O2), and decreases in glutathione (GSH) levels were attenuated by α-KG administration. These effects were remarkably eliminated by α-KG administration. Further study showed that the protective effect of α-KG was 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 in mice.Interpretation: Collectively, the data provided herein demonstrated that α-KG administration attenuated mucosal inflammation, barrier dysfunction, and gut microflora dysbiosis. This beneficial effect was associated with increased Lactobacillus levels, and regulated colon hyperplasia by the Wnt-Hippo signaling pathway.Funding: This work was supported by the National Natural Science Foundation of China (No. 31625025).Declaration of Interest: The authors declare no competing financial interests.Ethical Approval: All studies were performed according to protocols approved by the Institutional Animal Care and Use Committee of China Agricultural University (AW10210202-1-2).