Obesity is a world-wide epidemic and currently about 350 million people suffer from diabetes, resulting in more than 3 million deaths per year. While the gut microbiota has been identified as a contributing factor to obesity and insulin resistance in mice and humans, the underlying disease-causing mechanisms are yet to be defined. The aim of this proposal is to investigate the interactions between the gut microbiota and the intestinal mucosal barrier in metabolic disease.The human intestine is colonized by a complex microbial community with up to 1000 different species. While its composition is specific for each individual, a core gut microbiota is shared between humans. However, the composition of gut microbiota is altered in individuals who are obese, diabetic or suffer from cardiovascular disease.The high density of the gut microbiota provides a continuous challenge and potential threat to the gut epithelium. As only one single, mucus-covered cell layer separates microbes from human tissue the mucosal barrier is essential in preventing microbial translocation. One epithelial defense mechanism is the secretion of antimicrobial peptides (AMPs). These endogenous peptide antibiotics have broad-spectrum antimicrobial activity and can also modulate the composition of gut microbiota.In this proposal I will focus on the intestinal barrier between host and microbiota. I will test if and how the shifted microbial composition in metabolic diseases is associated with alterations in mucosal AMP production and function. Furthermore, I will analyze mucosa-associated microbiota in metabolic disease by using mouse models and samples from human patients. Also, I will compare the peptide repertoire in the mucus of different mouse models and human diabetes patients to identify alterations in the composition that are associated with metabolic disease.The planned investigations will help to better understand the relationship between the mucosal host barrier and metabolic disease.