Alpha-Ketoglutarate Attenuates Colitis in Mice by Increasing Lactobacillus Abundance 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 (H₂ O₂ ), 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.

Keywords: DSS-induced colitis; Lactobacillus; Wnt/β-catenin-Hippo signaling; alpha-ketoglutarate; intestinal stem cell.