Site-specific intestinal macrophage subtyping in health & inflammatory bowel diseases

• Applicant: Dr. Catharina Gutwein
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570489272

The pathogenesis of inflammatory bowel disease (IBD) involves complex interactions between genetics, environmental factors, gut microbiota, and immune dysregulation, but remains incompletely understood. Despite the availability of new therapies, a significant proportion of patients do not respond adequately, and the lack of reliable biomarkers complicates therapy selection. Furthermore, disease heterogeneity, particularly distinctions between ulcerative colitis (UC) and Crohn’s disease (CD) as well as disease location, such as ileal versus colonic involvement, critically impacts disease progression and therapeutic outcomes. However, how the anatomical site of inflammation shapes local immune responses remains largely unexplored. Emerging evidence suggests that macrophages may play a key role as site-specific regulators of tissue homeostasis and inflammation. We hypothesize that intestinal macrophages act as initiators and drivers of inflammation in IBD and contribute to site-specific differences in disease behavior. This project will address three main objectives: (1) To map site-specific macrophage populations in healthy intestine by applying single-cell RNA sequencing, flow cytometry, spatial transcriptomics, and multiplexed histology on biopsies from the right and left colon and ileum. By this, we will establish a comprehensive atlas of macrophage heterogeneity across the gastrointestinal tract. (2) To define IBD-specific alterations in macrophage populations by comparing inflamed and uninflamed areas from UC and CD patients. This will clarify how local inflammation affects macrophage states and functions. (3) To investigate macrophages as predictive markers for therapy response. By profiling intestinal macrophages before and during IL-23 blockade in a prospective cohort of CD patients, we aim to determine whether site-specific macrophage signatures correlate with endoscopic outcomes. The proposed study will generate an unprecedentedly detailed map of GI tissue macrophages in IBD by integrating spatial and single-cell technologies. This approach will facilitate a more profound comprehension of their spatial and functional heterogeneity, thereby elucidating fundamental principles of intestinal immune regulation in chronic intestinal inflammation in IBD.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Saurabh Mehandru