The gastrointestinal mucus system plays a crucial role in protecting the gut from bacterial invasion and maintaining homeostasis. Mucins, large glycosylated proteins, form the mucus layer, which is composed of transmembrane mucins and secreted gel-forming mucins produced by goblet cells. The small intestine has a single unattached mucus layer, while the stomach and colon have two layers: an inner, attached layer and an outer, loose layer. In cystic fibrosis, the inner mucus layer becomes attached, leading to intestinal manifestations. The stomach's mucus layer acts as a diffusion barrier for hydrochloric acid, and the colon's mucus layer is essential for harboring commensal bacteria. Pathogenic organisms can penetrate the mucus layer, leading to infections. Cystic fibrosis patients often develop intestinal obstruction due to an altered mucus phenotype. Commensal bacteria in the colon are protected by the mucus layer, which also serves as a habitat and food source for these bacteria. In ulcerative colitis, defective function of the inner mucus layer may contribute to bacterial contact with the epithelium, triggering an inflammatory immune response. Understanding the gastrointestinal mucus system is crucial for developing novel therapeutic strategies in health and disease.The gastrointestinal mucus system plays a crucial role in protecting the gut from bacterial invasion and maintaining homeostasis. Mucins, large glycosylated proteins, form the mucus layer, which is composed of transmembrane mucins and secreted gel-forming mucins produced by goblet cells. The small intestine has a single unattached mucus layer, while the stomach and colon have two layers: an inner, attached layer and an outer, loose layer. In cystic fibrosis, the inner mucus layer becomes attached, leading to intestinal manifestations. The stomach's mucus layer acts as a diffusion barrier for hydrochloric acid, and the colon's mucus layer is essential for harboring commensal bacteria. Pathogenic organisms can penetrate the mucus layer, leading to infections. Cystic fibrosis patients often develop intestinal obstruction due to an altered mucus phenotype. Commensal bacteria in the colon are protected by the mucus layer, which also serves as a habitat and food source for these bacteria. In ulcerative colitis, defective function of the inner mucus layer may contribute to bacterial contact with the epithelium, triggering an inflammatory immune response. Understanding the gastrointestinal mucus system is crucial for developing novel therapeutic strategies in health and disease.