Innate immunity of the gut epithelium: Blowing in the WNT?

Intestinal epithelial cells need to be able to launch a quick and adequate immune response against pathogens, while tolerating commensals. This delicate balance requires a tight control over the activation of the NFκB and Interferon pathways to prevent chronic inflammation. Simultaneously, intestinal stem cell maintenance and differentiation are strictly regulated by the WNT/β-catenin and Bone Morphogenetic Protein signaling pathways to allow proper tissue homeostasis. There is emerging evidence that these cell identity and innate immunity pathways are molecularly intertwined, which may have implications for our mechanistic understanding of intestinal diseases such as inflammatory bowel disease and colorectal cancer. Here, we provide a comprehensive overview of the most important molecular interactions between these pathways. We identify the current gaps in our knowledge, and we propose promising areas for future research, in particular organoid research combined with single cell sequencing technologies.