<b>Sialic acid-responsive</b> <i> <b>Parabacteroides</b> </i> <b>is linked to gut barrier integrity in older adults</b>

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 <i>Parabacteroides</i> showed a strong negative association with barrier dysfunction. <i>In vitro</i> assays showed that three <i>Parabacteroides</i> lineages predominant in older adults, including <i>P. merdae</i>, enhanced the intestinal barrier integrity in a viability-dependent manner. Fecal sialic acid (Neu5Ac) levels were positively correlated with the abundance of <i>Parabacteroides</i>. Mediation analysis further indicated that <i>Parabacteroides</i> 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 <i>Parabacteroides</i> growth. Transcriptomic analysis of <i>P. merdae</i> 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, <i>Parabacteroides</i> 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.