Zinc Alleviates Gut Barrier Dysfunction by Promoting the Methylation of AKT

Abstract Zinc plays a crucial role in the gut barrier function and are widely used for the prevention of bowel disease. However, the mechanism via which zinc supplementation exerts this regulatory effect is unclear. The present study identifies and characterizes the zinc‐responsive activation of AKT and demonstrates its function in alleviating gut barrier dysfunction. Mechanistically, zinc increased intracellular SAM production, a methyl donor, by promoting the activation of the metallochaperone ZNG1‐METAP1 complex. Subsequently, zinc facilitates methylation (symmetrical dimethylarginine, SDMA) of AKT at residues R391 and R15, which is facilitated by PRMT5. The AKT ^SDMA modification promotes AKT translocation from the cytoplasm to the plasma membrane and its interaction with mTORC2, ultimately promoting AKT activation and cell proliferation. Notably, histidine has an antagonistic effect on zinc‐induced the AKT activation, cell proliferation, and gut barrier improvement by chelating zinc. These results demonstrate that zinc activates AKT and alleviates gut barrier dysfunction by inducing activation of the ZNG1‐METAP1‐PRMT5‐AKT ^SDMA pathway, and highlight that limiting histidine intake may have effective therapeutic potential for bowel diseases such as Crohn's disease and Ulcerative colitis.