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) and magnesium (Mg)]. 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 absorption. We show that the butyrate concentration in the colon negatively correlates with serum Mg levels in wildtype mice. Moreover, Na-butyrate significantly inhibited Mg uptake in Caco-2 cells, while Ca 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 uptake by butyrate preceded these consequences. Importantly, electrophysiological examinations demonstrated that intracellular butyrate directly reduced the activity of the heteromeric Mg channel complex, transient receptor potential melastatin (TRPM)6/7. Blocking cellular butyrate uptake prevented its inhibitory effect on Mg uptake, demonstrating that butyrate acts intracellularly. Our work identified butyrate as novel regulator of intestinal Mg uptake that works independently from metabolic regulation. This finding further highlights the role of microbial fermentation in the regulation of mineral absorption.