Microbiota-produced immune regulatory bile acid metabolites control central nervous system autoimmunity
The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3<sup>+</sup> regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells. We validated our human findings in a preclinical model of MS by showing that DCA/LCA administration prevents experimental autoimmune encephalomyelitis (EAE) by dampening Th17 cell differentiation and the effector phenotype of myelin-reactive T cells. Our data highlight the key role of immune regulatory BAMs for the prevention of central nervous system (CNS) autoimmunity.
Authors
- Marta Lo Conte (ORCID: https://orcid.org/0000-0001-7640-1888)
- Annapaola Andolfo (ORCID: https://orcid.org/0000-0002-0566-2391)
- Federica Ungaro (ORCID: https://orcid.org/0000-0001-5395-7795)
- Vittorio Martinelli (ORCID: https://orcid.org/0000-0002-5987-5739)
- Vittoria Palmieri
- Denise Drago (ORCID: https://orcid.org/0000-0003-1363-5518)
- Francesco Asnicar (ORCID: https://orcid.org/0000-0003-3732-1468)
- Martina Antonini Cencicchio
- Federico Montini (ORCID: https://orcid.org/0000-0002-8367-0741)
- Alessandra Mandelli (ORCID: https://orcid.org/0000-0002-6494-7776)
- Roberto Furlan (ORCID: https://orcid.org/0000-0001-7376-9425)
- Radmila Pavlović (ORCID: https://orcid.org/0000-0002-2128-4589)
- Nicola Segata (ORCID: https://orcid.org/0000-0002-1583-5794)
- Marika Falcone (ORCID: https://orcid.org/0000-0001-6080-5351)
- Luca Massimino (ORCID: https://orcid.org/0000-0003-3975-9148)
- Annamaria Finardi (ORCID: https://orcid.org/0000-0002-7909-2600)
Institutions
- Vita-Salute San Raffaele University (IT)
- University of Trento (IT)
- IRCCS Ospedale San Raffaele (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102028
- Citations
- 19
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 15.31
Funders
- National Multiple Sclerosis Society