Bridging of host-microbiota tryptophan partitioning by the serotonin pathway in fungal pneumonia

Giorgia Renga, Fiorella D’Onofrio, Marilena Pariano, Roberta Galarini, Carolina Barola, Claudia Stincardini, Marina M. Bellet, Helmut Ellemunter, Cornelia Lass-Flörl, Claudio Costantini, Valerio Napolioni, Allison K. Ehrlich, Cinzia Antognelli, Massimo Fini, Enrico Garaci, Emilia Nunzi and Luigina Romani ()
Additional contact information
Giorgia Renga: University of Perugia
Fiorella D’Onofrio: University of Perugia
Marilena Pariano: University of Perugia
Roberta Galarini: Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche “Togo Rosati,”
Carolina Barola: Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche “Togo Rosati,”
Claudia Stincardini: University of Perugia
Marina M. Bellet: University of Perugia
Helmut Ellemunter: CF Centre, Medical University Innsbruck
Cornelia Lass-Flörl: Innsbruck Medical University
Claudio Costantini: University of Perugia
Valerio Napolioni: University of Camerino
Allison K. Ehrlich: University of California
Cinzia Antognelli: University of Perugia
Massimo Fini: University San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele
Enrico Garaci: University San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele
Emilia Nunzi: University of Perugia
Luigina Romani: University of Perugia

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxytryptamine (5-HT) pathway in calibrating host and microbial Trp metabolism during Aspergillus fumigatus pneumonia. We found that 5-HT produced by mast cells essentially contributed to pathogen clearance and immune homeostasis in infection by promoting the host protective indoleamine-2,3-dioxygenase 1/kynurenine pathway and limiting the microbial activation of the indole/aryl hydrocarbon receptor pathway. This occurred via regulation of lung and intestinal microbiota and signaling pathways. 5-HT was deficient in the sputa of patients with Cystic fibrosis, while 5-HT supplementation restored the dysregulated Trp partitioning in murine disease. These findings suggest that 5-HT, by bridging host-microbiota Trp partitioning, may have clinical effects beyond its mood regulatory function in respiratory pathologies with an inflammatory component.

Date: 2023
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DOI: 10.1038/s41467-023-41536-8

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