Fecal neuraminidase correlates with inflammatory signatures and microbiome shifts in preclinical Crohn’s disease

The mucus layer, rich in mucin glycoproteins, serves as a critical barrier to microbial invasion. Neuraminidases cleave terminal sialic acids from mucin glycans, a process that may influence mucus integrity, epithelial exposure to microbial antigens, and mucosal immune responses, making fecal neuraminidase activity a biologically relevant functional readout of host-microbe interactions in the context of Crohn’s disease (CD) pathogenesis. We evaluated whether fecal neuraminidase activity is associated with future CD risk and examine its relationships with inflammatory and microbial signatures relevant to early disease development. Within the prospective GEM cohort, 69 individuals who later developed CD were matched to 69 healthy first-degree relative controls. Fecal neuraminidase activity was measured using a fluorometric assay. Conditional logistic regression assessed its association with future CD risk. Partial Spearman correlations evaluated relationships with 446 serum proteins (OLINK), followed by pathway enrichment analysis, and with fecal calprotectin (FCP) and gut microbial composition (16S rRNA sequencing). Fecal neuraminidase activity was positively associated with future CD (OR = 1.541; 95% CI: 1.05–2.25; p = 0.026). Proteins correlated with neuraminidase activity were enriched in immune and inflammatory pathways. Neuraminidase activity was positively correlated positively with FCP (p ≤ 0.05), and its association with future CD was attenuated after adjustment for FCP. Fourteen microbial taxa were significantly correlated with neuraminidase activity (q ≤ 0.05). Fecal neuraminidase activity's relationships with inflammatory markers and microbial taxa support its potential relevance as a functional marker of host-microbe alterations during preclinical CD.