A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis
Abstract Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of...
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Nature Portfolio
2024-03-01
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Online Access: | https://doi.org/10.1038/s41598-024-57400-8 |
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author | Teresa Zelante Giuseppe Paolicelli Francesca Fallarino Marco Gargaro Gianluca Vascelli Marco De Zuani Jan Fric Petra Laznickova Marcela Hortova Kohoutkova Antonio Macchiarulo Daniela Dolciami Giuseppe Pieraccini Lorenzo Gaetani Giulia Scalisi Caterina Trevisan Barbara Frossi Carlo Pucillo Antonella De Luca Emilia Nunzi Roberta Spaccapelo Marilena Pariano Monica Borghi Francesca Boscaro Riccardo Romoli Andrea Mancini Lucia Gentili Giorgia Renga Claudio Costantini Matteo Puccetti Stefano Giovagnoli Maurizio Ricci Martina Antonini Paolo Calabresi Paolo Puccetti Massimiliano Di Filippo Luigina Romani |
author_facet | Teresa Zelante Giuseppe Paolicelli Francesca Fallarino Marco Gargaro Gianluca Vascelli Marco De Zuani Jan Fric Petra Laznickova Marcela Hortova Kohoutkova Antonio Macchiarulo Daniela Dolciami Giuseppe Pieraccini Lorenzo Gaetani Giulia Scalisi Caterina Trevisan Barbara Frossi Carlo Pucillo Antonella De Luca Emilia Nunzi Roberta Spaccapelo Marilena Pariano Monica Borghi Francesca Boscaro Riccardo Romoli Andrea Mancini Lucia Gentili Giorgia Renga Claudio Costantini Matteo Puccetti Stefano Giovagnoli Maurizio Ricci Martina Antonini Paolo Calabresi Paolo Puccetti Massimiliano Di Filippo Luigina Romani |
author_sort | Teresa Zelante |
collection | DOAJ |
description | Abstract Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative l-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR–mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases. |
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issn | 2045-2322 |
language | English |
last_indexed | 2024-04-24T19:56:34Z |
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spelling | doaj.art-ef3dd28764624aada7153b8839b12acc2024-03-24T12:20:26ZengNature PortfolioScientific Reports2045-23222024-03-0114111610.1038/s41598-024-57400-8A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosisTeresa Zelante0Giuseppe Paolicelli1Francesca Fallarino2Marco Gargaro3Gianluca Vascelli4Marco De Zuani5Jan Fric6Petra Laznickova7Marcela Hortova Kohoutkova8Antonio Macchiarulo9Daniela Dolciami10Giuseppe Pieraccini11Lorenzo Gaetani12Giulia Scalisi13Caterina Trevisan14Barbara Frossi15Carlo Pucillo16Antonella De Luca17Emilia Nunzi18Roberta Spaccapelo19Marilena Pariano20Monica Borghi21Francesca Boscaro22Riccardo Romoli23Andrea Mancini24Lucia Gentili25Giorgia Renga26Claudio Costantini27Matteo Puccetti28Stefano Giovagnoli29Maurizio Ricci30Martina Antonini31Paolo Calabresi32Paolo Puccetti33Massimiliano Di Filippo34Luigina Romani35Department of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaInternational Clinical Research Centre, St. Anne’s University Hospital BrnoInternational Clinical Research Centre, St. Anne’s University Hospital BrnoInternational Clinical Research Centre, St. Anne’s University Hospital BrnoInternational Clinical Research Centre, St. Anne’s University Hospital BrnoDepartment of Pharmaceutical Science, University of PerugiaDepartment of Pharmaceutical Science, University of PerugiaMass Spectrometry Center (CISM), University of FlorenceDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medical and Biological Science, University of UdineDepartment of Medical and Biological Science, University of UdineDepartment of Medical and Biological Science, University of UdineDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaMass Spectrometry Center (CISM), University of FlorenceMass Spectrometry Center (CISM), University of FlorenceDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Pharmaceutical Science, University of PerugiaDepartment of Pharmaceutical Science, University of PerugiaDepartment of Pharmaceutical Science, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaUnità di Neurologia, Fondazione Policlinico Universitario Agostino Gemelli, IRCCSDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaDepartment of Medicine and Surgery, University of PerugiaAbstract Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative l-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR–mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.https://doi.org/10.1038/s41598-024-57400-8Mast cellsAryl hydrocarbon receptorSerotonin3-IAldMultiple sclerosis |
spellingShingle | Teresa Zelante Giuseppe Paolicelli Francesca Fallarino Marco Gargaro Gianluca Vascelli Marco De Zuani Jan Fric Petra Laznickova Marcela Hortova Kohoutkova Antonio Macchiarulo Daniela Dolciami Giuseppe Pieraccini Lorenzo Gaetani Giulia Scalisi Caterina Trevisan Barbara Frossi Carlo Pucillo Antonella De Luca Emilia Nunzi Roberta Spaccapelo Marilena Pariano Monica Borghi Francesca Boscaro Riccardo Romoli Andrea Mancini Lucia Gentili Giorgia Renga Claudio Costantini Matteo Puccetti Stefano Giovagnoli Maurizio Ricci Martina Antonini Paolo Calabresi Paolo Puccetti Massimiliano Di Filippo Luigina Romani A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis Scientific Reports Mast cells Aryl hydrocarbon receptor Serotonin 3-IAld Multiple sclerosis |
title | A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis |
title_full | A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis |
title_fullStr | A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis |
title_full_unstemmed | A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis |
title_short | A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis |
title_sort | microbially produced ahr ligand promotes a tph1 driven tolerogenic program in multiple sclerosis |
topic | Mast cells Aryl hydrocarbon receptor Serotonin 3-IAld Multiple sclerosis |
url | https://doi.org/10.1038/s41598-024-57400-8 |
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