Influence of the microbiota on intestinal dendritic cells and its impact on Inflammatory Bowel Disease

• Applicant: Lis Noelia Velasquez, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546219389

Intestinal dendritic cells (DCs) play a pivotal role in orchestrating the delicate balance between anti-inflammatory and pro-inflammatory responses within the gastrointestinal tract. Not only must they interact with the complex microbial milieu but at the same time prime and modulate the differentiation of T cells. So far, the study of intestinal DCs has been encumbered by their limited numbers and phenotypic overlap with other myeloid cells. Recent advancements in single-cell sequencing technology, particularly in the analysis of intestinal lesions in patients with Inflammatory Bowel Disease (IBD), have provided valuable insights. Yet, the precise influence of the local microenvironment, and in particular the microbiota, on the functional and phenotypic attributes of intestinal DCs is not completely understood. Additionally, the triggers promoting either pro- or anti-inflammatory responses remain elusive. Thus, the principal hypothesis of this project is that the intestinal microbiota is one of the main factors driving the phenotype and function of intestinal DCs. Preliminary data indicates that the intestinal microbiota influences the severity of colitis and has a major impact on the transcriptome of colonic DCs. Furthermore, different microbiota compositions differentially induced the up-regulation of IBD risk loci in DCs in the distal colon. However, the mechanisms mediating this effect and its consequence in intestinal homeostasis and disease remain unclear. Thus, the overarching objectives of this project are: 1) To study the DC phenotype in the distal colon under homeostatic conditions in mice with predefined microbiota compositions; 2) To evaluate alterations in the DC phenotype in the distal colon during intestinal inflammation in mice with predefined microbiota compositions; 3) To investigate the effect of the microbiota derived from IBD patients on distal colon DCs. The methodology that will be used to understand the relationship between the microbiota and DCs in homeostasis and during inflammation, encompasses transcriptomic, metabolomic, and proteomic analyses of intestinal DCs and the colonic tissue coupled with an in-depth study of the microbiota. Additionally, the interaction of DCs with other intestinal cell types, and in particular T cells, will be studied using a new mouse model developed in our lab, the CD11c-Cherry-labeling mouse. To translate the findings to the human setting IBD patient samples will be analyzed via single-cell sequencing in combination with metabolomics and 16s rRNA sequencing of the microbiota. Finally, the validity of the findings will be evaluated using patient-specific gnotobiotic mice.

• DFG Programme: Research Grants