Cysteine Exerts an Essential Role in Maintaining Intestinal Integrity and Function Independent of Glutathione.

Abstract

Enteral feeding is a primary source of cysteine for intestinal mucosa given negligible transsulfuration activity in enterocytes and furthermore very few cysteine uptake from arterial blood. This study aims to explore the role of cysteine in maintaining intestinal integrity and function. The intestinal porcine enterocytes (IPEC-J2) are cultured in a cysteine-deprived medium with or without glutathione supplementation upon the inhibitions of glutathione synthesis or degradation. As a result, cysteine deprivation impairs mitochondrial function, suppresses mechanistic target of rapamycin (mTOR) signaling, and activates general control nonderepressible 2 (GCN2) signaling, and might lead to resultant ferroptosis. Glutathione supplementation can restore the impairment through degrading into cysteine, while glutathione synthesis inhibition does not disturb the role of cysteine in keeping the intestinal epithelial cells. Furthermore, piglets are fed with cysteine-deficient, -adequate, and -surplus diet for 28 days as a porcine model. In this study, it is evidenced that intestinal integrity and individual growth benefit from adequate dietary cysteine. Adequate dietary cysteine supply is essential for intestinal mucosal integrity, epithelial cell turnover, and amino acid sensing as well as optimal individual growth. Cysteine exerts its role independent of glutathione and glutathione restores the impairment of cysteine-deprivation on intestinal mucosal through degrading into cysteine.