Alpha-Ketoglutarate Attenuates Colitis in Mice by Increasing Lactobacillus Abundance 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 (alpha-KG) can alleviate colitis in mice. Methods and results: Six-week-old male C57BL/6 mice supplemented with or without 0.5% alpha-KG (delivered in the form of sodium salt) are subjected to drinking water or 2.5% DSS to induce colitis. The results show that alpha-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 (H2O2), and decreases in glutathione (GSH) levels are attenuated by alpha-KG administration. Further study shows that the protective effect of alpha-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 alpha-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.

Automated summary

The administration of alpha-ketoglutarate (alpha-KG) can alleviate the severity of colitis in mice by restoring gut barrier integrity, increasing Lactobacillus levels, and regulating colon hyperplasia through the Wnt-Hippo signaling pathway.