Mechanisms of proton pump inhibitor-induced hypomagnesemia

Proton pump inhibitors (PPIs) reliably suppress gastric acid secretion and are therefore the first-line treatment for gastric acid-related disorders. Hypomagnesemia (serum magnesium [Mg²⁺ ] <0.7 mmol/L) is a commonly reported side effect of PPIs. Clinical reports demonstrate that urinary Mg²⁺ excretion is low in PPI users with hypomagnesemia, suggesting a compensatory mechanism by the kidney for malabsorption of Mg²⁺ in the intestines. However, the exact mechanism by which PPIs cause impaired Mg²⁺ absorption is still unknown. In this review, we show that current experimental evidence points toward reduced Mg²⁺ solubility in the intestinal lumen. Moreover, the absorption pathways in both the small intestine and the colon may be reduced by changes in the expression and activity of key transporter proteins. Additionally, the gut microbiome may contribute to the development of PPI-induced hypomagnesemia, as PPI use affects the composition of the gut microbiome. In this review, we argue that the increase of the luminal pH during PPI treatment may contribute to several of these mechanisms. Considering the fact that bacterial fermentation of dietary fibers results in luminal acidification, we propose that targeting the gut microbiome using dietary intervention might be a promising treatment strategy to restore hypomagnesemia in PPI users.