Protease-serpin-microbiome interactions in inflammatory bowel disease: toward integrated biomarkers of gut health

Proteolytic imbalance involving host and microbial serine proteases and their inhibitors (serpins) contributes to intestinal barrier disruption and chronic inflammation in inflammatory bowel disease (IBD). However, the interplay among these components remains insufficiently characterized. Here, we survey 13,304 publications over five decades, to map protease-serpin-microbiome literature in IBD. Our analysis reveals a fragmented literature structure, with uneven coverage and limited cross-domain integration among host proteases, microbial proteases, and inhibitory pathways. We synthesize evidence linking these components to intestinal barrier integrity, mucosal immunity, extracellular-matrix remodeling, and microbial ecology. Considering the protease-serpin-microbiome axis may provide an integrative direction for future studies of IBD pathogenesis, including the investigation of mechanisms underlying disease heterogeneity, prioritizing future biomarker and therapeutic studies.