Medicago Sativa L. Saponin‐Driven Lactobacillus Intestinalis Restores Intestinal Stemness in Naturally Aged Mice via the Bile Acid‐FXR‐Wnt Signaling Axis

Aging is recognized as a significant risk factor for chronic diseases. The decline in intestinal stem cells function is a critical contributor to intestinal aging, resulting in impaired intestinal homeostasis and increased vulnerability to age-related diseases. Medicago sativa L. (alfalfa) saponin are plant-derived bioactive compounds that are shown to have benefits in regulating oxidative stress and gut microbiota. However, the potential of alfalfa saponin (AS) to modulate intestinal aging and enhance intestinal stemness to maintain homeostasis remains insufficiently explored. In this study, the effects of AS on intestinal stemness in naturally aged mice and its underlying mechanisms involving gut microbiota regulation are examined. Antibiotic-mediated depletion of intestinal bacteria and fecal microbiota transplantation are employed to determine the specific role of the gut microbiota in mediating the effects of AS. Comprehensive multi-omics analyses revealed that AS significantly increased the abundance of Lactobacillus intestinalis (L. intestinalis). Notably, L. intestinalis is found to possess bile acids metabolic capabilities, producing ursodeoxycholic acid, which functions as an FXR antagonist to activate the Wnt signaling pathway and enhance intestinal stemness, thereby supporting intestinal homeostasis. These findings are validated in both intestinal organoids and naturally aged mice models. This study provides the first identification of a complete functional axis by which the metabolites of AS and L. intestinalis modulate intestinal stemness to mitigate intestinal aging, offering insights for the development of innovative natural product-based therapeutic strategies to promote healthy aging.