1/1
2 files

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

figure
posted on 02.06.2021, 22:04 by Emelyne Lécuyer, Tiphaine Le Roy, Aurélie Gestin, Amélie Lacombe, Catherine Philippe, Maharajah Ponnaiah, Jean-Baptiste Huré, Magali Fradet, Farid Ichou, Samira Boudebbouze, Thierry Huby, Emmanuel Gautier, Moez Rhimi, Emmanuelle Maguin, Nathalie Kapel, Philippe Gérard, Nicolas Venteclef, Michèle Garlatti, Benoit Chassaing, Philippe Lesnik
Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes.

The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice) are challenged with a high-fat diet.

Those mice display resistance to DIO and metabolic alterations. The DIO-resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses.

Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic disease management.

Funding

This study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), the Fondation de France (00029519), and the Institute of Cardiometabolism and Nutrition (IHU-ICAN, ANR-10-IAHU-05). E.L. was supported by the Fondation Lefoulon Delalande/Institut de France and the Region Ile-de-France CORDDIM.

History