Characterization of intestine-specific TRPM6 knockout C57BL/6 J mice: effects of short-term omeprazole treatment.

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg balance. Disturbance in Mg balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4 days) omeprazole treatment on intestinal Mg malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6 and 50% Vill1-TRPM6) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20 mg/kg bodyweight omeprazole or placebo for 4 days. Vill1-TRPM6 mice had a significantly lower Mg absorption compared to control TRPM6 mice, accompanied by lower Mg serum levels, and urinary Mg excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn transporter Slc30a10. However, no changes in Mn serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg homeostasis as no changes in serum Mg and total Mg were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6 mice have a lower Mg absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg absorption in both Vill1-TRPM6 and TRPM6 mice. This suggests that TRPM6-mediated Mg absorption in the intestines is not affected by short-term PPI administration.