The mucus layer coating the gastrointestinal tract serves as the first line of innate host defense, primarily due to the secretory products of intestinal goblet cells. Goblet cells synthesize and secrete mucins (MUC2), trefoil factor peptides (TFF), resistin-like molecule β (RELMβ), and Fc-γ binding protein (Fcgbp). MUC2 forms trimers through disulfide bonding and crosslinking with TFF and Fcgbp, creating a highly viscous extracellular layer. The mucus layer has two layers: an outer "loose" layer that interacts with commensal bacteria and an inner "adherent" layer that is largely free of bacteria. Defective mucus layers, such as those caused by mutations in MUC2 or core mucin glycosyltransferase enzymes, lead to increased bacterial adhesion, intestinal permeability, and susceptibility to colitis. Changes in mucin gene expression and glycan structures are observed in cancers of the intestine, contributing to their development and progression. Further research is needed to understand the complex interactions between mucus layers, microbiota, epithelial cells, and the immune system, which may lead to novel therapeutic approaches for intestinal diseases.The mucus layer coating the gastrointestinal tract serves as the first line of innate host defense, primarily due to the secretory products of intestinal goblet cells. Goblet cells synthesize and secrete mucins (MUC2), trefoil factor peptides (TFF), resistin-like molecule β (RELMβ), and Fc-γ binding protein (Fcgbp). MUC2 forms trimers through disulfide bonding and crosslinking with TFF and Fcgbp, creating a highly viscous extracellular layer. The mucus layer has two layers: an outer "loose" layer that interacts with commensal bacteria and an inner "adherent" layer that is largely free of bacteria. Defective mucus layers, such as those caused by mutations in MUC2 or core mucin glycosyltransferase enzymes, lead to increased bacterial adhesion, intestinal permeability, and susceptibility to colitis. Changes in mucin gene expression and glycan structures are observed in cancers of the intestine, contributing to their development and progression. Further research is needed to understand the complex interactions between mucus layers, microbiota, epithelial cells, and the immune system, which may lead to novel therapeutic approaches for intestinal diseases.