2. Academic Validation
  3. Effect of the gut microbiota-derived tryptophan metabolite indole-3-acetic acid in pneumonia

Effect of the gut microbiota-derived tryptophan metabolite indole-3-acetic acid in pneumonia

  • Nat Commun. 2025 Sep 29;16(1):8565. doi: 10.1038/s41467-025-63611-y.
Robert F J Kullberg 1 2,  Christine C A van Linge 3 4,  Bastiaan W Haak 3 4,  Prasanjit S Paul 3 4,  Joe M Butler 3 4,  Nora Wolff 3 4,  Tjitske S R van Engelen 3 4,  Jonne J Sikkens 5,  Marije K Bomers 6,  Antoine Lefèvre 7,  Olaf L Cremer 8,  Joris J T H Roelofs 9,  Bruno Sovran 10 11 12,  René van den Wijngaard 10,  Alex F de Vos 3 4,  Wouter J de Jonge 10 13,  Tom van der Poll 3 4 6,  W Joost Wiersinga 3 4 6
Affiliations

Affiliations

  • 1 Center for Infection and Molecular Medicine (CIMM), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. [email protected].
  • 2 Amsterdam institute for Immunology and Infectious diseases, Amsterdam, the Netherlands. [email protected].
  • 3 Center for Infection and Molecular Medicine (CIMM), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 4 Amsterdam institute for Immunology and Infectious diseases, Amsterdam, the Netherlands.
  • 5 Department of Internal Medicine, Section Acute and General Internal Medicine, Amsterdam UMC, Amsterdam, The Netherlands.
  • 6 Department of Internal Medicine, Division of Infectious Diseases, Amsterdam UMC, Amsterdam, The Netherlands.
  • 7 UMR 1253, iBrain, INSERM, University of Tours, Tours, France.
  • 8 Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 9 Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 10 Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 11 Department of Paediatric Surgery, Amsterdam Reproduction and Development Research Institute, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • 12 Emma Center for Personalized Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 13 Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany.
PMID: 41022731 DOI: 10.1038/s41467-025-63611-y
Abstract

Gut microbiota influence the severity of pneumonia by producing metabolites that enhance systemic and pulmonary immune responses. Preclinical studies suggested that gut microbiota-derived indoles have protective effects against numerous diseases, including influenza and abdominal infections. However, the precise role of tryptophan metabolites during pneumonia is unknown. Here, we perform translational analyses in a large general-population cohort (n = 13,464), critically ill patients with severe community-acquired pneumonia (CAP; n = 158; NCT01905033), a randomized human intervention trial on antibiotic-mediated microbiota modulation (NCT03051698), and mice to investigate the effects of tryptophan metabolites, specifically indole-3-acetic acid (IAA), on pneumonia. In the population-based cohort, baseline IAA is associated with a higher risk of future hospital admission for pneumonia (cause-specific hazard ratio 1.15, 95% confidence interval 1.09-1.22 p < 0.0001). In patients with severe CAP higher levels of IAA are associated with increased mortality, independent from potential confounders (hazard ratio 1.30 per log2 increase, 95% confidence interval 1.02-1.68, p = 0.037). In a mouse model of Bacterial pneumonia, IAA supplementation aggravates pulmonary damage while reducing systemic dissemination, which is mediated by the Aryl Hydrocarbon Receptor (AhR) and increased release of Reactive Oxygen Species from neutrophils. In summary, these findings from general population and severe pneumonia cohorts, and murine pneumonia experiments, show that the gut microbiota-derived tryptophan metabolite IAA affects pneumonia, suggesting that various indoles may have diverging, context-dependent effects.

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