Abstract
Aging is frequently accompanied by inflammaging-a chronic, low-grade inflammatory state that contributes to functional decline and disease risk. Disruption of the intestinal barrier is increasingly being recognized as a key driver of inflammaging; however, its relationship with the gut microbiota in older adults remains poorly understood. Here, we demonstrate a significant association of intestinal barrier dysfunction markers with systemic inflammatory markers using a cross-sectional study in this population. Notably, the genus Parabacteroides showed a strong negative association with barrier dysfunction. In vitro assays showed that three Parabacteroides lineages predominant in older adults, including P. merdae, enhanced the intestinal barrier integrity in a viability-dependent manner. Fecal sialic acid (Neu5Ac) levels were positively correlated with the abundance of Parabacteroides. Mediation analysis further indicated that Parabacteroides significantly mediated the association between fecal sialic acid and intestinal barrier markers. Culture experiments showed that both sialic acid and mucin, which is rich in terminal sialyl residues, promoted Parabacteroides growth. Transcriptomic analysis of P. merdae cultured with sialic acid revealed upregulation of genes for sialidases, transporters, and enzymes, consistent with sialic acid catabolism and transport, suggesting utilization of mucin-derived sialic acid. Together, these findings indicate that in older adults, Parabacteroides is linked to the intestinal barrier integrity and responds to mucin-associated sialic acid, supporting a model wherein host-derived glycans foster barrier-protective microbes to promote healthy aging. The study findings provide avenues for devising strategies for maintaining the intestinal barrier integrity and reducing age-related inflammation, which may ultimately contribute to the prevention of inflammaging.