Effect of the gut microbiota-derived tryptophan metabolite indole-3-acetic acid in pneumonia
Robert F. J. Kullberg, Christine C. A. van Linge, Bastiaan W. Haak, Prasanjit S. Paul, Joe M. Butler, Nora Wolff, Tjitske S. R. van Engelen, Jonne J. Sikkens, Marije K. Bomers, Antoine Lefèvre, Olaf L. Cremer, Joris J. T. H. Roelofs, Bruno Sovran, René van den Wijngaard, Alex F. de Vos, Wouter J. de Jonge, Tom van der Poll, W. Joost Wiersinga
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.