Butyrate reduces cellular magnesium absorption independently of metabolic regulation in Caco-2 human colon cells

Digestion of dietary fibers by gut bacteria has been shown to stimulate intestinal mineral absorption [e.g., calcium (Ca(2+)) and magnesium (Mg(2+))]. Although it has been suggested that local pH and short-chain fatty acid (SCFA) concentrations determine divalent cation absorption, the exact molecular mechanisms are still unknown. Therefore, this study aimed to determine the effects of SCFAs on intestinal Mg(2+) absorption. We show that the butyrate concentration in the colon negatively correlates with serum Mg(2+) levels in wildtype mice. Moreover, Na-butyrate significantly inhibited Mg(2+) uptake in Caco-2 cells, while Ca(2+) uptake was unaffected. Although Na-butyrate significantly lowered total ATP production rate, and resulted in increased phosphorylation of AMP-activated protein kinase (AMPK), inhibition of Mg(2+) uptake by butyrate preceded these consequences. Importantly, electrophysiological examinations demonstrated that intracellular butyrate directly reduced the activity of the heteromeric Mg(2+) channel complex, transient receptor potential melastatin (TRPM)6/7. Blocking cellular butyrate uptake prevented its inhibitory effect on Mg(2+) uptake, demonstrating that butyrate acts intracellularly. Our work identified butyrate as novel regulator of intestinal Mg(2+) uptake that works independently from metabolic regulation. This finding further highlights the role of microbial fermentation in the regulation of mineral absorption.