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.

Center of Functional Genomics C U R Ge F University of Perugia 06132 Perugia Italy

Department of Medical and Biological Science University of Udine 33100 Udine Italy

Department of Medicine and Surgery University of Perugia Piazza Lucio Severi 1 06132 Perugia Italy

Department of Pharmaceutical Science University of Perugia 06132 Perugia Italy

Institute of Hematology and Blood Transfusion U Nemocnice 2094 1 128 20 Prague Czech Republic

International Clinical Research Centre Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

International Clinical Research Centre St Anne's University Hospital Brno Brno Czech Republic

Interuniversity Consortium for Biotechnology 34149 Trieste Italy

Mass Spectrometry Center University of Florence 50139 Florence Italy

Unità di Neurologia Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

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$a A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis / $c T. Zelante, G. Paolicelli, F. Fallarino, M. Gargaro, G. Vascelli, M. De Zuani, J. Fric, P. Laznickova, MH. Kohoutkova, A. Macchiarulo, D. Dolciami, G. Pieraccini, L. Gaetani, G. Scalisi, C. Trevisan, B. Frossi, C. Pucillo, A. De Luca, E. Nunzi, R. Spaccapelo, M. Pariano, M. Borghi, F. Boscaro, R. Romoli, A. Mancini, L. Gentili, G. Renga, C. Costantini, M. Puccetti, S. Giovagnoli, M. Ricci, M. Antonini, P. Calabresi, P. Puccetti, M. Di Filippo, L. Romani

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$a 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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