Fecal Detection of Calprotectin Subunits Links Inflammatory Bowel Disease Activity With Chronicity of Intestinal Inflammation

TL;DR

This study shows that detecting S100A9 dimers in stool can indicate IBD activity and suggests new ways to diagnose and treat intestinal inflammation.

Contribution

The study reveals the inflammatory roles of S100A8 and S100A9 homodimers in IBD, beyond the known calprotectin complex.

Findings

Fecal S100A9 dimers correlate with IBD disease activity when calprotectin levels are low.

S100A8 and S100A9 homodimers worsen intestinal inflammation in mouse models.

Pharmacologic inhibition of S100A9 reduces chronic colitis in mice.

Abstract

Quantification of the human S100A8/S100A9 tetrameric protein complex in stool, referred to as fecal calprotectin, is an extensively validated biomarker supporting the diagnosis and management of gastrointestinal diseases. Here, we studied the quaternary protein structures (termed configuration) of S100A8 and S100A9 and their biological function in inflammatory bowel diseases (IBD).

We dissected fecal S100A8 and S100A9 configurations in patients with IBD by size-exclusion chromatography coupled with tandem mass spectrometry and systematically defined human S100A8 and S100A9 homodimer functions compared with the calprotectin heterotetramer (CP) in the intestine of mice and in human epithelium and T cells. Moreover, we report a protein interaction network of fecal S100A8 and S100A9 in IBD.

Stool from patients with active IBD contained abundant S100A8 and S100A9 dimers besides CP. Fecal S100A9 detection associated with clinical and endoscopic disease activity in IBD patients with low CP concentration. Oral exposure to human recombinant S100A8 and S100A9 homodimers, but not to CP, worsened intestinal inflammation in toxic and genetic mouse models. Functional profiling revealed that human S100A8 and S100A9 homodimers enhanced activation of cluster of differentiation 4+ and 8+ T cells, which promoted experimental colitis. In turn, genetic inactivation of S100a9 protected against experimental enteritis and colitis, and pharmacologic inhibition of S100A9 ameliorated chronic colitis.

Collectively, this study links the detection of fecal S100A9 dimers with clinical and endoscopic disease activity in IBD and identifies inflammatory actions of S100A8 and S100A9 homodimers in the intestine. Our findings pave the way for novel diagnostic and therapeutic approaches in patients with inflammatory diseases of the intestine.

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