l-Malic Acid Enhances Intestinal Stem Cell Expansion and Barrier Function via the Sirt2/β-Catenin Signaling Pathway

The continuous proliferation and differentiation of intestinal stem cells are essential for maintaining homeostasis and barrier function. l-Malic acid (L-MA), a key intermediate in host and microbial metabolism, has emerged as a potential regulator of intestinal health. In this study, oral administration of L-MA improved intestinal structure and barrier function and the activity of intestinal stem cells. Mechanistically, L-MA reduced intracellular NAD⁺ levels, which in turn inhibited the expression and enzymatic activity of Sirt2. This further enhanced the acetylation and activation of β-catenin, thereby upregulating the expression of ZO-1, PCNA, Occludin, and Claudin1. Using a small intestinal organoid model, we confirmed that L-MA increased organoid budding rate and formation efficiency and inhibited Sirt2 expression. In conclusion, L-MA regulates ISC expansion and improves intestinal barrier function by modulating NAD⁺ levels via the Sirt2/β-catenin signaling pathway. These findings provide a novel strategy for maintaining intestinal health by targeting intestinal epithelial cell homeostasis.