Macrophages and mTORC1 signaling in colitis and cancer

Macrophages are central cells for the maintenance of tissue integrity and for immune responses in the gastrointestinal tract. A dysregulation of macrophage function can promote inflammatory bowel disease that promotes the development of colitis-associated cancer. The central aim of the research proposal is to investigate the role of mTORC1 for colon homeostasis and inflammation during colitis and colitis-associated cancer. We will focus on the role of mTORC1 in macrophages and its relevance for metabolic and immune cross-talk. The elucidation of how macrophages metabolically coordinate immune responses might have fundamental implications for our understanding of immunity. Assessing the role of mTORC1 for macrophage function and metabolism in the colon may provide novel therapeutic strategies to control chronic inflammatory disorders or cancer.

The intestine is one of the most rapidly renewing tissues in the human body. Every few days, millions of epithelial cells lining the gut are replaced to maintain an intact barrier against microbes and harmful substances. Failure of this renewal process contributes to inflammatory bowel diseases such as colitis and increases the risk of colorectal cancer. While immune cells are well known for fighting infections, growing evidence suggests that they also play important roles in maintaining normal tissue function. However, the molecular mechanisms behind this supportive role have remained poorly understood. In this project, we investigated how macrophages, a major immune cell population in the intestine, help to preserve intestinal tissue health. We focused on a central metabolic signaling pathway called mTORC1, which allows cells to sense nutrient availability and adjust their metabolism accordingly. Using genetic mouse models and experimental colitis, we discovered that activation of mTORC1 in macrophages protects the intestine from inflammatory damage. Mice with enhanced mTORC1 signaling in macrophages developed milder disease and recovered faster after injury. Importantly, these mice were also protected in a model of inflammation-associated colorectal cancer, showing a reduced tumor burden in the colon. Mechanistically, we found that macrophages directly support nearby epithelial cells by supplying them with small metabolic molecules. In particular, macrophages with active mTORC1 produced increased amounts of polyamines, naturally occurring metabolites that promote cell growth. By analyzing healthy colon tissue, we observed that macrophages are positioned in close contact with intestinal crypts, the sites where epithelial stem and progenitor cells reside. Polyamines released by macrophages are taken up by epithelial cells and enable them to reprogram their own metabolism in a way that accelerates cell division and tissue repair. This metabolic cooperation becomes especially important during phases of proliferative stress, such as inflammation-induced colitis, when rapid regeneration of the epithelial barrier is essential. Our findings therefore reveal a division of labor between immune cells and tissue cells: macrophages provide metabolic support, while epithelial cells execute efficient regeneration. Together, this coordinated response helps maintain intestinal integrity and protects the organism from chronic inflammation. Beyond polyamines, we initiated an untargeted metabolomics approach to explore whether macrophages secrete additional metabolites that influence epithelial growth and tissue homeostasis. This screen identified several promising candidate molecules, which are currently being investigated in more detail. Overall, our work uncovers an unexpected role of macrophages as metabolic caretakers of the intestine. Rather than acting solely as immune defenders, macrophages actively fuel tissue regeneration and stability. These insights broaden our understanding of immune-tissue communication and may open new therapeutic avenues for inflammatory bowel disease and colorectal cancer.