The intestinal microbiota plays a key role in health and disease, often through direct bacterial interactions with the host intestinal (immune) cells or by released bacterial metabolites. Our main goal is to understand the molecular mechanisms that underly pathogenic host-microbiota interactions. An important focus is a group of ‘pathogenic’ commensals called pathobionts, which often live within the intestinal mucus layer in close proximity or attached to intestinal epithelial cells. The interactions of these pathobionts with the host epithelium and immune system are still mostly unclear but believed to dramatically impact on various disease, including inflammatory bowel disease, colorectal cancer and metabolic syndrome. By unraveling the molecular mechanisms behind pathological host-microbiota interactions, we aim to pave the road for the development of novel therapeutic approaches.