Enteroendocrine cells allow the gut to sense nutrients, bacterial products, and other environmental cues and respond by releasing hormones that modulate satiety, food preferences, and even mood. These cells are thought to primarily communicate with nerve cells indirectly via hormone secretion; however, Diego Bohórquez and colleagues at Duke University identified an enteroendocrine cellular structure, known as a neuropod, which directly interacts with nerve cells. By fluorescently labeling specific enteroendocrine cell populations in mice, they demonstrated that nerves in the gut mucosa directly contact the enteroendocrine neuropod. Moreover, enteroendocrine cells express pre- and post-synaptic proteins, indicating that they can form synapses with nerve cells. Finally, enteroendocrine cells were able to transmit a fluorescently labeled form of the rabies virus to adjacent nerve cells, indicating the presence of a functional neural circuit. The accompanying movie shows a purified enteroendocrine cell and trigeminal (TG) neuron making a connection (Video 1) and an enteroendocrine cell seeking to make a connection to putative axon of a TG (Video 2).
Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit’s functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems.
Diego V. Bohórquez, Rafiq A. Shahid, Alan Erdmann, Alex M. Kreger, Yu Wang, Nicole Calakos, Fan Wang, Rodger A. Liddle