The EPIC-Norfolk Study
Effect of the gut microbiota-derived tryptophan metabolite indole-3-acetic acid in pneumonia.
Nature communications 2025 ; 16: 8565.
Kullberg RFJ, van Linge CCA, Haak BW, Paul PS, Butler JM, Wolff N, van Engelen TSR, Sikkens JJ, Bomers MK, Lefèvre A, Cremer OL, Roelofs JJTH, Sovran B, van den Wijngaard R, de Vos AF, de Jonge WJ, van der Poll T, and Wiersinga WJ
DOI : 10.1038/s41467-025-63611-y
PubMed ID : 41022731
PMCID : PMC12480536
URL : https://www.nature.com/articles/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.