Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection
Séverine Heumel,
Vinícius de Rezende Rodovalho,
Charlotte Urien,
Florian Specque,
Patrícia Brito Rodrigues,
Cyril Robil,
Lou Delval,
Valentin Sencio,
Amandine Descat,
Lucie Deruyter,
Stéphanie Ferreira,
Marina Gomes Machado,
Adeline Barthelemy,
Fabiola Silva Angulo,
Joel. T Haas,
Jean François Goosens,
Isabelle Wolowczuk,
Corinne Grangette,
Yves Rouillé,
Ghjuvan Grimaud,
Marie Lenski,
Benjamin Hennart,
Marco Aurélio Ramirez Vinolo,
François Trottein
Affiliations
Séverine Heumel
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Vinícius de Rezende Rodovalho
Laboratory of Immunoinflammation, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
Charlotte Urien
Genoscreen, Lille, France
Florian Specque
Biomathematica, Rue des Aloes, Quartier Balestrino, Ajaccio, France
Patrícia Brito Rodrigues
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Cyril Robil
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Lou Delval
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Valentin Sencio
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Amandine Descat
Univ. Lille, CHU Lille, EA 7365 – GRITA – Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France
Lucie Deruyter
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Stéphanie Ferreira
Genoscreen, Lille, France
Marina Gomes Machado
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Adeline Barthelemy
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Fabiola Silva Angulo
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Joel. T Haas
Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, Lille, France
Jean François Goosens
Univ. Lille, CHU Lille, EA 7365 – GRITA – Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France
Isabelle Wolowczuk
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Corinne Grangette
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Yves Rouillé
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
Ghjuvan Grimaud
Biomathematica, Rue des Aloes, Quartier Balestrino, Ajaccio, France
Marie Lenski
Univ. Lrille, CHU Lille, Service de toxicologie et Génopathies, ULR 4483 – IMPECS – IMPact de l’Environnement Chimique sur la Santé humaine, Lille, France
Benjamin Hennart
Univ. Lrille, CHU Lille, Service de toxicologie et Génopathies, ULR 4483 – IMPECS – IMPact de l’Environnement Chimique sur la Santé humaine, Lille, France
Marco Aurélio Ramirez Vinolo
Laboratory of Immunoinflammation, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
François Trottein
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
ABSTRACTThe gut-to-lung axis is critical during respiratory infections, including influenza A virus (IAV) infection. In the present study, we used high-resolution shotgun metagenomics and targeted metabolomic analysis to characterize influenza-associated changes in the composition and metabolism of the mouse gut microbiota. We observed several taxonomic-level changes on day (D)7 post-infection, including a marked reduction in the abundance of members of the Lactobacillaceae and Bifidobacteriaceae families, and an increase in the abundance of Akkermansia muciniphila. On D14, perturbation persisted in some species. Functional scale analysis of metagenomic data revealed transient changes in several metabolic pathways, particularly those leading to the production of short-chain fatty acids (SCFAs), polyamines, and tryptophan metabolites. Quantitative targeted metabolomics analysis of the serum revealed changes in specific classes of gut microbiota metabolites, including SCFAs, trimethylamine, polyamines, and indole-containing tryptophan metabolites. A marked decrease in indole-3-propionic acid (IPA) blood level was observed on D7. Changes in microbiota-associated metabolites correlated with changes in taxon abundance and disease marker levels. In particular, IPA was positively correlated with some Lactobacillaceae and Bifidobacteriaceae species (Limosilactobacillus reuteri, Lactobacillus animalis) and negatively correlated with Bacteroidales bacterium M7, viral load, and inflammation markers. IPA supplementation in diseased animals reduced viral load and lowered local (lung) and systemic inflammation. Treatment of mice with antibiotics targeting IPA-producing bacteria before infection enhanced viral load and lung inflammation, an effect inhibited by IPA supplementation. The results of this integrated metagenomic-metabolomic analysis highlighted IPA as an important contributor to influenza outcomes and a potential biomarker of disease severity.
