The gastrointestinal (GI) tract extracts nutrients from ingested meals while protecting the organism from infectious agents frequently present in meals. Consequently, most animals conduct the entire digestive process within the GI tract while keeping the luminal contents entirely outside the body, separated by the tightly sealed GI epithelium. Therefore, like skin and oral cavity, the GI tract must sense luminal contents’ chemical and physical properties to optimize digestion. Specialized sensory enteroendocrine cells (EECs) in GI epithelium intimately interact with luminal contents.