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A crucial mechanism of intestinal defense includes the production and secretion of host defense peptides (HDPs). HDPs control pathogens and commensals at the intestinal interface by direct killing, by sequestering vital ions, or by causing bacterial cells to aggregate in the mucus layer. Accordingly, the combined activity of various HDPs neutralizes gut bacteria before reaching the mucosa and thus helps to maintain the homeostatic balance between the host and its microbes at the mucosal barrier. Defects in the mucosal barrier have been associated with various diseases that are on the rise in the Western world. These include metabolic diseases, such as obesity and type 2 diabetes, and inflammatory intestinal disorders, including ulcerative colitis and Crohn's disease, the two major entities of inflammatory bowel disease. While the etiology of these diseases is multifactorial, highly processed Western-style diet (WSD) that is rich in carbohydrates and fat and low in dietary fiber content, is considered to be a contributing lifestyle factor. As such, WSD does not only profoundly affect the resident microbes in the intestine, but can also directly alter HDP function, thereby potentially contributing to intestinal mucosal barrier dysfunction. In this review we aim to decipher the complex interaction between diet, microbiota, and HDPs. We discuss how HDP expression can be modulated by specific microbes and their metabolites as well as by dietary factors, including fibers, lipids, polyphenols and vitamins. We identify several dietary compounds that lead to reduced HDP function, but also factors that stimulate HDP production in the intestine. Furthermore, we argue that the effect of HDPs against commensal bacteria has been understudied when compared to pathogens, and that local environmental conditions also need to be considered. In addition, we discuss the known molecular mechanisms behind HDP modulation. We believe that a better understanding of the diet-microbiota-HDP interdependence will provide insights into factors underlying modern diseases and will help to identify potential dietary interventions or probiotic supplementation that can promote HDP-mediated intestinal barrier function in the Western gut.

Does an Apple a Day Also Keep the Microbes Away? The Interplay Between Diet, Microbiota, and Host Defense Peptides at the Intestinal Mucosal Barrier