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

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.