Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota That Protects From Metabolic Diseases

Excess chronic contact between microbial motifs and intestinal immune cells is 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 in these changes is still poorly documented. To address this question, we challenged transgenic mice with enhanced DC life span and immunogenicity (DC^hBcl-2 mice) 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. DC^hBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function, which is associated with strong intestinal IgA, T helper 17, and regulatory T-cell immune responses. Microbiota composition and function analyses reveal that the DC^hBcl-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 wild-type mice, demonstrating that maintenance of DCs' tolerogenic ability sustains a microbiota able to drive DIO resistance. The tolerogenic function of DCs is revealed as a new potent target in metabolic disease management.