Interaction between Batf3 dependent dendritic cells and the microbiota during experimental colitis

• Applicant: Professor Dr. Kai Hildner
• Subject Area: Gastroenterology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280526818

The entity of intestinal microbes, also called microbiota, exerts critical functions, e.g. digestive properties and maintenance of barrier integrity in favor of the host. In order to control the close interaction between commensal flora and host cells a sophisticated immunological network has developed at mucosal surfaces to prevent on the one hand uncontrolled dissemination of microbiota beyond the intestine and on the other hand overshooting immune responses against apathogenic commensals. Mucosal dendritic cells (DCs) crucially contribute to the generation of an antimicrobial immune response and the maintenance of gut homeostasis. Previously, own work identified the transcription factor Batf3 as a central regulator of lymphoid resident CD8alphapos. and mucosal CD103pos.CD11bneg.DC development. Batf3 deficient mice therefore represent an excellent in vivo mouse model system allowing the analysis of the role of Batf3 dependent DCs during intestinal inflammation and infections. Interestingly, Batf3 deficient mice are relatively resistant to intestinal infection with Citrobacter rodentium, a rodent pathogen mirroring human pathogenic E. coli (e.g. EHEC) mediated colitis. Results from flora depletion studies via long term antibiotic treatment imply that the infection resistance is predominately mediated by the preexisting microbial colonization in the absence of Batf3. Interestingly cohousing and stool transplantation respectively are able to transfer relative protection against Citrobacter rodentium infection from Batf3 deficient to wildtype mice. Data derived from the noninfectious experimental transfer colitis model also demonstrate that colitis susceptibility is communicable via transfer of the intestinal flora. Preliminary analyses of the stool by next generation sequencing show that Batf3 deficiency is associated with significant alterations of intestinal microbiota composition compared to controls. Together these results show that Batf3 dependent DCs critically influence the composition or function of the gut microbiota and that the modulation seems to account for both the decreased infectious and increased immune-mediated colitis susceptibility in the absence of Batf3.So far studies addressing the consequences of selective DC deficiencies on the composition and function of the intestinal microbiota are limited. Therefore analyses addressing the contribution of Batf3 dependent DCs to the composition of gut microbiota on the one hand and the nature of the microbiota-dependent immunological effector mechanisms underlying the infection resistance against Citrobacter rodentium in Batf3 deficient mice on the other hand are in the center of the proposed research project. Results from these studies will provide the basis to develop targeted strategies to intentionally modulate the composition or function of the microbiota and of the immune system respectively as treatment options of infectious and inflammatory disease states of the gut.

• DFG Programme: Research Grants