Deficient Active Transport Activity in Healing Mucosa After Mild Gastric Epithelial Damage

Background Peptic ulcers recur, suggesting that ulcer healing may leave tissue predisposed to subsequent damage. In mice, we have identified that the regenerated epithelium found after ulcer healing will remain abnormal for months after healing. Aim To determine whether healed gastric mucosa has altered epithelial function, as measured by electrophysiologic parameters. Method Ulcers were induced in mouse gastric corpus by serosal local application of acetic acid. Thirty days or 8 months after ulcer induction, tissue was mounted in an Ussing chamber. Transepithelial electrophysiologic parameters (short-circuit current, I-sc. resistance, R) were compared between the regenerated healed ulcer region and the non-ulcerated contralateral region, in response to luminal hyperosmolar NaCl challenge (0.5 M). Results In unperturbed stomach, luminal application of hyperosmolar NaCl transiently dropped I-sc followed by gradual recovery over 2 h. Compared to the starting baseline I-sc, percent I-sc recovery was reduced in 30-day healing mucosa, but not at 8 months. Prior to NaCl challenge, a lower baseline I-sc was observed in trefoil factor 2 (TFF2) knockout (KO) versus wild type (WT), with no I-sc recovery in either non-ulcerated or healing mucosa of KO. Inhibiting Na/H exchanger (NHE) transport in WT mucosa inhibited I-sc recovery in response to luminal challenge. NHE2-KO baseline I-sc was reduced versus NHE2-WT. In murine gastric organoids, NHE inhibition slowed recovery of intracellular pH and delayed the repair of photic induced damage. Conclusion Healing gastric mucosa has deficient electrophysiological recovery in response to hypertonic NaCl. TFF2 and NHE2 contribute to I-sc regulation, and the recovery and healing of transepithelial function.