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 diseases1,2. The quaternary protein structures (called configuration here) of S100A8 and S100A9 and their biological function in the human intestine is unknown. This study unravels a diagnostic value for fecal S100A9 detection in IBD and identifies pleiotropic inflammatory mechanisms of S100A8 and S100A9 homodimers in the intestine.