2. Academic Validation
  3. Fecal Detection of Calprotectin Subunits Links Inflammatory Bowel Disease Activity With Chronicity of Intestinal Inflammation

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

  • Gastroenterology. 2025 Nov 26:S0016-5085(25)05987-6. doi: 10.1053/j.gastro.2025.08.040.
Almina Jukic 1,  Richard Hilbe 2,  Luis Zundel 1,  Peter Willeit 3,  Klaus Faserl 4,  Christina Plattner 5,  Andreas Zollner 1,  Moritz Meyer 1,  Kerstin Siegmund 6,  Victoria Klepsch 6,  Valentin Marteau 5,  Arnau Vich Vila 7,  Julian Schwärzler 1,  Kathrin Vouk 1,  Anna Kozsar 1,  Dietmar Rieder 8,  Amos Weichberger 9,  Bettina Sarg 4,  Felix Grabherr 1,  Lisa Mayr 1,  Patrizia Moser 10,  Niloofar Nemati 5,  Sabine Scholl-Bürgi 11,  Daniela Karall 11,  Georg F Vogel 12,  Lina Welz 13,  Denise Aldrian 11,  Robert Koch 1,  Alexandra Pfister 1,  Qitao Ran 14,  Arthur Kaser 15,  Richard S Blumberg 16,  Ivan Tancevski 2,  Felix Sommer 13,  Petra Bacher 9,  Stefan Schreiber 13,  Philip Rosenstiel 13,  Konrad Aden 13,  Gottfried Baier 6,  Latifa Bakiri 17,  Thomas Müller 11,  Günter Weiss 2,  TRR241 IBDome Consortium,  Rinse K Weersma 7,  Zlatko Trajanoski 5,  Erwin F Wagner 28,  Herbert Tilg 29,  Timon E Adolph 30
Affiliations

Affiliations

  • 1 Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
  • 2 Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.
  • 3 Institute of Clinical Epidemiology, Public Health, Health Economics, Medical Statistics and Informatics, Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
  • 4 Biocenter, Protein Core Facility, Institute of Medical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
  • 5 Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.
  • 6 Institute of Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria.
  • 7 Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center of Groningen, Groningen, the Netherlands.
  • 8 Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria; Biocenter, Bioinformatics Core Facility, Medical University of Innsbruck, Innsbruck, Austria.
  • 9 Institute of Clinical Molecular Biology, Christian Albrecht University Kiel and Schleswig-Holstein University Hospital, Kiel, Germany; Institute of Immunology, Christian Albrecht University Kiel and Schleswig-Holstein University Hospital, Kiel, Germany.
  • 10 INNPATH, Innsbruck Medical University Hospital, Innsbruck, Austria.
  • 11 Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
  • 12 Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria; Institute of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria.
  • 13 Institute of Clinical Molecular Biology, Christian Albrecht University Kiel and Schleswig-Holstein University Hospital, Kiel, Germany.
  • 14 Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas.
  • 15 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
  • 16 Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 17 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • 18 Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany.
  • 19 Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany; Institute of Immunology, Christian-Albrecht University of Kiel and Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
  • 20 Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 21 Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany.
  • 22 Institute of Microbiology, Infectious Diseases and Immunology Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
  • 23 Berlin Institute für Gesundheitsforschung, Medizinische System Biologie, Charité- Universitätsmedizin Berlin, Berlin, Germany.
  • 24 Institute of Immunology, Christian-Albrecht University of Kiel and Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
  • 25 Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max Delbrück Center für Molekulare Medizin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 26 Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany.
  • 27 Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 28 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; Department of Dermatology, Medical University of Vienna, Vienna, Austria.
  • 29 Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: [email protected].
  • 30 Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: [email protected].
PMID: 41295942 DOI: 10.1053/j.gastro.2025.08.040
Abstract

Background & aims: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Calprotectin; Crohn's Disease; Inflammatory Bowel Diseases; Intestinal Inflammation; S100A8; S100A9; Ulcerative Colitis.

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