Epithelial Toll-like receptors and their role in gut homeostasis and disease

The human gastrointestinal tract is colonized by trillions of microorganisms that interact with the host to maintain structural and functional homeostasis. Acting as the interface between the site of the highest microbial burden in the human body and the richest immune compartment, a single layer of intestinal epithelial cells specializes in nutrient absorption, stratifies microorganisms to limit colonization of tissues and shapes the responses of the subepithelial immune cells. In this Review, we focus on the expression, regulation and functions of Toll-like receptors (TLRs) in the different intestinal epithelial lineages to analyse how epithelial recognition of bacteria participates in establishing homeostasis in the gut. In particular, we elaborate on the involvement of epithelial TLR signalling in controlling crypt dynamics, enhancing epithelial barrier integrity and promoting immune tolerance towards the gut microbiota. Furthermore, we comment on the regulatory mechanisms that fine-tune TLR-driven immune responses towards pathogens and revisit the role of TLRs in epithelial repair after injury. Finally, we discuss how dysregulation of epithelial TLRs can lead to the generation of dysbiosis, thereby increasing susceptibility to colitis and tumorigenesis. Interactions between intestinal epithelial cells, the gut microbiota and immune cells have a key role in maintaining gut homeostasis. This Review describes how epithelial recognition of bacteria through Toll-like receptors participates in establishing homeostasis, and how dysregulation of these receptors can lead to dysbiosis, increasing susceptibility to colitis and tumorigenesis. Key points The intestinal epithelium provides a physical and immune barrier between the host and the gut microbiota that is dynamically regulated through the production of metabolites and the signalling of pattern recognition receptors. Toll-like receptors (TLRs) are microbial-induced proteins that are expressed in most epithelial cell lineages and have important antimicrobial functions. Tight regulation mechanisms prevent excessive responses towards commensal microorganisms. Activation of TLRs controls crypt dynamics by altering proliferation and apoptosis in stem cells and transit amplifying cells. Differentiation into secretory lineages, particularly via the NOTCH pathway, occurs in a myeloid differentiation primary response protein 88 (MYD88) and TLR4-dependent manner. TLR recognition of microbial motifs enhances the int