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

Area of Science:

• Gastroenterology
• Cell Biology
• Metabolism

Background:

• Intestinal stem cells (ISCs) are crucial for gut homeostasis and barrier integrity.
• l-Malic acid (L-MA) is a metabolite involved in host and microbial processes, with potential roles in intestinal health.

Purpose of the Study:

• To investigate the effects of L-MA on intestinal stem cell activity and barrier function.
• To elucidate the molecular mechanisms underlying L-MA's impact on the intestine.

Main Methods:

• Oral administration of L-MA in a study model.
• Analysis of intestinal structure, barrier function, and ISC activity.
• Investigation of intracellular NAD+ levels, Sirtuin 2 (Sirt2) expression and activity, and beta-catenin signaling.
• Utilizing a small intestinal organoid model to assess L-MA's effects.

Main Results:

• Oral L-MA improved intestinal structure, barrier function, and ISC activity.
• L-MA reduced intracellular NAD+ levels, leading to Sirt2 inhibition.
• This pathway enhanced beta-catenin acetylation and activation, upregulating tight junction proteins (ZO-1, Occludin, Claudin1) and proliferation markers (PCNA).
• L-MA increased organoid budding and formation efficiency while decreasing Sirt2 expression in vitro.

Conclusions:

• L-Malic acid regulates ISC expansion and enhances intestinal barrier function.
• The mechanism involves modulating NAD+ levels via the Sirt2/beta-catenin signaling pathway.
• L-MA presents a novel strategy for promoting intestinal health by targeting epithelial cell homeostasis.