In homeostatic conditions (left), the microbiota resides exclusively in the outer mucus layer. When the barrier is disrupted, for example, through injury, impaired mucus production or chronic inflammation (middle), bacteria, including members of the microbiota and pathobionts, can establish contact with epithelial cells and even invade crypts and interact with stem cells. In addition, distinct pathogens have evolved mechanisms to breach even an intact mucus barrier to make contact with host cells (right). These bacteria can also penetrate glands and adhere to stem cells. AMPs: antimicrobial peptides.