Wenyang Yiqi Formula improves Na + /H + ion transport by inhibiting NHE3 via activation of gastrin/CCKBR pathway

Abstract Background: STC is a common digestive disorder and WYF is a Chinese medicine used to treat it. NHE3 is a protein that helps absorb sodium ions and its inhibition has been linked to various diarrheal diseases. There is little research on the effects of WYF on NHE expression and the treatment of STC, and the mechanism behind it is not understood. Objective: This study aimed to investigate the effects of the WYF on Na+/H+ ion transport in vivo and in vitro and to uncover the mechanism of the WYF in treating STC. Methods: The effectiveness of WYF in treating STC was tested on rats with induced STC and Caco-2 cells in a laboratory setting. The study compared the impact of WYF on several factors, including the rate of intestinal transit, colon tissue pathology, characteristics of feces, and stool volume among five groups (n=6/group). The researchers also evaluated the effects of WYF on cell viability, NHE3 activity and expression, and markers in two signaling pathways (gastrin/CCKBR and PI3K/PLC/PKC). Results: WYF improved the rate of intestinal transit and colon tissue pathology in STC rats, and reduced cell viability and NHE3 activity and expression in Caco-2 cells. The concentration of gastrin and the level of CCKBR increased with WYF treatment, while NHE3 activity had opposite trends in response to WYF and the sh-CCKBR group. Adding gastrin reversed these effects in the sh-CCKBR group. The activity of NHE3 was decreased in the WYF (20%)+gastrin (300 nmol) group, but significantly upregulated in the sh-CCKBR group with or without serum containing 20% WYF, which was reversed after adding gastrin. The ratios of p-PI3K to PI3K, p-PLC to PLC, and p-PKC to PKC in the serum containing 20% WYF were significantly increased, but decreased in the LY294002 group. After adding serum containing WYF, the reduction of these ratios was reversed. The activity of NHE3 had opposite trends to the ratios of p-PI3K to PI3K, p-PLC to PLC, and p-PKC to PKC. Conclusion: The WYF can be used to treat STC, possibly by improving Na+/H+ ion transport through inhibiting NHE3, activating the gastrin/CCKBR pathway, and PI3K/PLC/PKC-dependent pathways.