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 Mg²⁺ balance. Disturbance in Mg²⁺ 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 Mg²⁺ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6^-/-) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6^fl/fl 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 ²⁵Mg²⁺ absorption compared to control TRPM6^fl/fl mice, accompanied by lower Mg²⁺ serum levels, and urinary Mg²⁺ 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 Mn²⁺ transporter Slc30a10. However, no changes in Mn²⁺ serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg²⁺ homeostasis as no changes in serum ²⁵Mg²⁺ and total Mg²⁺ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6^-/- mice have a lower Mg²⁺ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg²⁺ absorption in both Vill1-TRPM6^-/- and TRPM6^fl/fl mice. This suggests that TRPM6-mediated Mg²⁺ absorption in the intestines is not affected by short-term PPI administration.