Our intestinal tract is colonized by a myriad of microbes that exceed our body cells in number and coding capacity and have important metabolic and signaling functions. Analysis of the diversity of these microbes inside revealed more than 1000 species, some of which have developed intimate interactions that are operating at the mucus interface separating the intestinal and microbial cells. Notably, we sustain and stimulate these interactions by feeding our microbes inside by the production of large amounts of mucus that equal the undigested components of our diet in caloric value. The understanding of the mucosal interactions is of great importance as they affect our immune system, signal to the brain-gut axis and provide a protective barrier against pathogens. Hence, this project aims to obtain fundamental understanding in the diversity and function of our microbes inside with a focus on mucus-binding bacteria that are either indigenous in the human intestine or ingested as part of our diet. The project will capitalize on (i) the recently developed high-throughput functional (meta)genomics approaches for human subjects, (ii) the genomic characterization of the mucus-degrading species Akkermansia muciniphila, an emerging biomarker for a healthy intestine, and (iii) the genome-driven discovery that the paradigm probiotic, Lactobacillus rhamnosus GG (LGG), contains cell-wall extended pili that strongly bind mucus and signal to human cells. A novel screening system will allow isolation of LGG derivatives with altered mucus-binding that will be instrumental in cause effect and other mechanistic studies. Moreover, the results will contribute to detailed insight in how our microbes inside develop mutualistic interactions, allowing for the design of new food-based approaches.