2. Academic Validation
  3. Immunometabolic reprogramming of macrophages by gut microbiota-derived cadaverine controls colon inflammation

Immunometabolic reprogramming of macrophages by gut microbiota-derived cadaverine controls colon inflammation

  • Cell Host Microbe. 2025 Sep 30:S1931-3128(25)00375-0. doi: 10.1016/j.chom.2025.09.009.
Rodrigo de Oliveira Formiga 1,  Qing Li 1,  Yining Zhao 2,  Márcio Augusto Campos Ribeiro 2,  Perle Guarino-Vignon 1,  Rand Fatouh 1,  Leonard Dubois 1,  Laura Creusot 1,  Virginie Puchois 1,  Salomé Amouyal 1,  Iria Alonso Salgueiro 1,  Marius Bredon 1,  Loïc Chollet 3,  Tatiana Ledent 4,  Cyril Scandola 5,  Jean-Philippe Auger 6,  Camille Danne 1,  Gerhard Krönke 7,  Emma Tkacz 1,  Patrick Emond 8,  Guillaume Chevreux 9,  Hang Phuong Pham 10,  Clément Pontoizeau 11,  Antonin Lamaziere 1,  Rafael José Argüello 12,  Nathalie Rolhion 1,  Marie-Laure Michel 3,  Timothy Wai 2,  Harry Sokol 13
Affiliations

Affiliations

  • 1 Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Paris 75012, France; Gut, Liver & Microbiome Research (GLIMMER) FHU, Paris, France.
  • 2 Mitochondrial Biology Unit, Institut Pasteur, CNRS UMR3691, Université Paris Cité, Paris 75015, France.
  • 3 Gut, Liver & Microbiome Research (GLIMMER) FHU, Paris, France; Université Paris-Saclay, INRAe, AgroParisTech, Micalis Institute, Jouy-en-Josas 78350, France.
  • 4 Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Paris 75012, France.
  • 5 Ultrastructural Bioimaging Unit, Institut Pasteur, Université Paris Cité, Paris 75015, France.
  • 6 Department of Internal Medicine 3, University of Erlangen-Nuremberg, Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 7 Department of Internal Medicine 3, University of Erlangen-Nuremberg, Universitätsklinikum Erlangen, Erlangen 91054, Germany; Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Deutsches Rheuma-Forschungszentrum Berlin, Berlin 10117, Germany.
  • 8 Département Métabolomique, Université de Tours, INSERM UMRS-1253, Plateforme Scientifique et Technique Analyse des Systèmes Biologiques, Tours 37000, France.
  • 9 Université Paris Cité, CNRS, UMRS-7592, ProteoSeine Core Facility, Institut Jacques Monod, Paris 75013, France.
  • 10 Parean Biotechnologies, Saint-Malo 35400, France.
  • 11 Pediatrics Department, Necker Hospital, APHP, Biochemistry, Metabolomics Unit, Reference Center for Inborn Error of Metabolism, University Paris Cité, Paris 75015, France; Inserm UMR_S1163, Institut Imagine, Paris 75015, France.
  • 12 Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille 13288, France.
  • 13 Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Paris 75012, France; Gut, Liver & Microbiome Research (GLIMMER) FHU, Paris, France; Université Paris-Saclay, INRAe, AgroParisTech, Micalis Institute, Jouy-en-Josas 78350, France; Gastroenterology Department, Saint-Antoine Hospital, APHP, Paris 75012, France. Electronic address: harry.sokol@gmail.com.
PMID: 41033313 DOI: 10.1016/j.chom.2025.09.009
Abstract

Cadaverine is a polyamine produced by the gut microbiota with links to health and disease, notably inflammatory bowel disease (IBD). Here, we show that cadaverine shapes monocyte-macrophage immunometabolism in a context- and concentration-dependent fashion to impact macrophage functionality. At baseline, cadaverine is taken up via L-lysine transporters and activates the thioredoxin system, while during inflammation, cadaverine signals through aconitate decarboxylase 1 (Acod1)-itaconate. Both pathways induce activation of transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which supports mitochondrial respiration and promotes immunoregulatory macrophage polarization. Conversely, under higher concentrations, cadaverine acts via histamine 4 receptor, leading to glycolysis-driven inflammation and pro-inflammatory functions in macrophages. Likewise, cadaverine exhibits paradoxical effects in experimental colitis, either protective or detrimental, evoking opposite fates on macrophages depending on levels dictated by Enterobacteriaceae. In IBD patients, elevated cadaverine correlated with higher flare risk. Our findings implicate cadaverine as a microbiota-derived metabolite manipulating macrophage energy metabolism with consequences in intestinal inflammation and implications for IBD pathogenesis.

Keywords

IBD; cadaverine; cell energy metabolism; gut microbiota; macrophage; metabolite; microbiome; monocyte.

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