Dietary N-acetylneuraminic acid maintains intestinal homeostasis and protects against aging- and inflammation-associated colonic dysfunction

Intestinal homeostasis is essential for systemic health and longevity, and its disruption contributes to colitis and age-related gut dysfunction. N-acetylneuraminic acid (Neu5Ac), a major form of sialic acid enriched in bird's nest and human milk, exhibits immunomodulatory and antioxidant properties, yet its physiological role in intestinal integrity remains unclear. Here, we demonstrate that oral Neu5Ac supplementation preserves intestinal homeostasis in both natural aging and dextran sulfate sodium (DSS)-induced colitis models. Neu5Ac enhanced epithelial barrier integrity, increased tight-junction proteins, and maintained mucosal architecture. It alleviated systemic and local inflammation by suppressing macrophage infiltration and polarization toward the pro-inflammatory phenotype while maintaining tissue-reparative macrophages. Neu5Ac also selectively enriched butyrate-producing bacterial taxa, including Butyricimonas synergistica and Parabacteroides goldsteinii, thereby increasing fecal butyrate levels, without globally altering microbial diversity. Mechanistically, transcriptomic profiling implicated the HIF-1 signaling pathway in mediating the anti-inflammatory effects of Neu5Ac. Consistently, Neu5Ac reduced colonic HIF-1α protein signals, predominantly localized to inflammatory cells, and suppressed HIF-1α expression in LPS-stimulated macrophages. Neu5Ac promoted epithelial regeneration and mitigated senescence-associated p53 activation, thereby restoring gut homeostasis. Importantly, Neu5Ac exhibited excellent biosafety in vivo. Together, these findings identify Neu5Ac as a bioactive nutritional molecule that sustains intestinal homeostasis through coordinated epithelial, immune, and microbial modulation, offering a promising preventive strategy against aging- and inflammation-driven intestinal disorders.