(i) A stimulus in the lumen, such as stretch or distension, results in the release of serotonin by the epithelial cells in the gut mucosa. (ii) The serotonin and mechanical stretch activate afferent neurons. These neurons, in turn, activate sensory afferent fibers that send projections into the submucosal and myenteric plexuses. This in turn activates two limbs of the peristaltic reflex. (iii) Upstream of the stimulus, interneurons synapse with and activate excitatory motor neurons that release acetylcholine and tachykinins to trigger smooth muscle contractions. (iv) Downstream of the stimulus, interneurons synapse with and activate inhibitory motor neurons that release NO and purines to trigger smooth muscle relaxation. The combination of upstream contraction and downstream relaxation creates a pressure gradient that drives the luminal contents from the proximal to the distal end of the gut. Colitis is characterized by increased serotonin availability, increased excitability of afferent neurons, facilitation of interneuronal synaptic activity, decreased purinergic neuromuscular transmission, and loss of myenteric neurons, which together lead to a mixture of overlapping excitatory and inhibitory motor outputs in the inflamed region (see Figure 2). EEC, enteroendocrine cell.