AT A GLANCE

A new study published in Advanced Science shows that the amino acid histidine adversely affects zinc’s function in alleviating gut barrier dysfunction.¹

“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,” explain study authors Cai et al. “The present study identifies and characterizes the zinc-responsive activation of AKT and demonstrates its function in alleviating gut barrier dysfunction.”

According to the authors, mechanistically, zinc increases intracellular the production of S-adenosyl methionine, a methyl donor, by promoting activation of the metallochaperone ZNG1–METAP1 complex. “Subsequently, zinc facilitates methylation (symmetrical dimethylarginine) of AKT at residues R391 and R15, which is facilitated by PRMT5,” they add. This 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.”

Further examination revealed that histidine chelates zinc, exerting an antagonistic effect on zinc-induced AKT activation, cell proliferation, and gut barrier improvement.

“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,” conclude the authors.

Reference

1.     Cai C, Zheng Y, Sun B, et al. Zinc alleviates gut barrier dysfunction by promoting the methylation of AKT (online ahead of print July 11, 2025). Adv Sci (Weinh).