Why Look Beyond Fecal Calprotectin? Fecal calprotectin (FC) is one of the most widely used noninvasive biomarkers in inflammatory bowel disease (IBD).
Why Look Beyond Fecal Calprotectin?
Fecal calprotectin (FC) is one of the most widely used noninvasive biomarkers in inflammatory bowel disease (IBD). It reflects intestinal inflammation through the detection of the S100A8/S100A9 heterotetramer, released primarily from neutrophils. However, FC measurement traditionally focuses on the tetrameric complex, without distinguishing between different molecular configurations of its subunits. Emerging evidence suggests that S100A8 and S100A9 homodimers may have distinct biological and inflammatory functions. In particular, fecal S100A9 has attracted attention as a potentially more sensitive indicator of disease activity and chronic intestinal inflammation. This study explores whether analysing these specific subunits can improve disease monitoring and uncover new therapeutic targets in IBD.
Summary
Using advanced proteomic analysis, investigators characterized the structural forms of S100A8 and S100A9 proteins present in stool from patients with inflammatory bowel disease. Besides the classic calprotectin heterotetramer, high levels of S100A8 and S100A9 homodimers were detected in active disease. Importantly, fecal S100A9 levels correlated strongly with clinical and endoscopic activity, even in patients with relatively low fecal calprotectin concentrations, suggesting added diagnostic sensitivity.
Functional experiments demonstrated that oral exposure to recombinant S100A8 or S100A9 homodimers, but not the calprotectin tetramer, aggravated intestinal inflammation in mouse models of colitis. Mechanistic studies showed that these homodimers enhance activation of CD4⁺ and CD8⁺ T cells, thereby amplifying inflammatory responses. Conversely, genetic deletion of S100a9 protected mice from experimental colitis, and pharmacologic inhibition of S100A9 significantly reduced chronic intestinal inflammation.
Together, these findings suggest that fecal S100A9 dimers represent both a novel biomarker and a potential therapeutic target in IBD, linking biomarker detection directly with pathogenic mechanisms of chronic intestinal inflammation.
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