It has long been known that the gut communicates with the brain via different pathways that include neuronal activation, the release of hormones and immune signals. Enteroendocrine cells (EECs)—scattered along the gastrointestinal tract between absorptive enterocytes—are involved in sensing luminal nutrients and bacteria and communicating this indirectly to the brain via the release of gut hormones (e.g. cholecystokinin). However, the underlying mechanisms that mediate the transduction of gut signals to the brain remain unidentified.
A new study, led by Dr. Diego V. Bohórquez from the departments of Medicine and Neurobiology at Duke University (North Carolina, USA), has demonstrated that a type of enteroendocrine cell in the gut layer called the neuropod cell communicates with sensory nerve fibers through direct cell-nerve contact.
In order to trace the circuit between EECs and nerves in vivo, the researchers used a modified fluorescent rabies virus that selectively infects EECs and spreads through synapses onto nerves. The virus, given to mice via enema, spread not only to sensory neurons in the colon, but also to vagal neurons projecting into the nucleus tractus solitarius of the brainstem. These findings show the existence of a neuroepithelial circuit that links the intestinal lumen with the brainstem with only one synapse.
On the other hand, the neuroepithelial circuit was reconstituted in vitro by coculturing single EECs with sensory neurons to test whether sugar was sensed by the vagus nerve directly or via EECs. Vagal neurons cultured alone did not respond to the glucose stimulus. In contrast, when the sensory neurons were cocultured with EECs, visible connections between the two cell types were made and glucose stimulated action potentials in the neurons.
Using optogenetics—a technique that uses flashes of light to monitor the activities of specific individual cells in genetically engineered animals—the researchers discovered both in vitro and in vivo that, in the presence of a photostimulus, glucose elicited excitatory postsynaptic currents as fast as 60ms in light-sensitive EECs. However, a light-inhibitory channel abolished glucose-stimulated activity in the vagal neurons in the presence of a photostimulus. These data show that EECs are required to rapidly transduce a glucose stimulus from gut to sensory neurons.
The existence of this gut-brain neural connection capable of rapidly transducing sensory signals from the gut to the brain was indeed supported by previous data. Other researchers had shown that hypothalamic neurons involved in the central control of feeding and energy expenditure were silenced within seconds of nutrients reaching the intestine.
Furthermore, by using a specific protein that fluoresces in the presence of glutamate, EECs were shown to release glutamate in the presence of a glucose stimulus. In addition, excitatory postsynaptic currents were suppressed in the presence of glutamate receptor blockers. These findings show that the neurotransmitter glutamate is used by EECs to rapidly transduce luminal stimuli to the brain.
Beyond secreting neuropeptides, the role of some EECs in conveying information about nutrients in the gut to the brain by releasing quick-acting neurotransmitters led researchers to call them “neuropod cells”. The researchers explain that this mechanism may be the first to sense nutrients that immediately reach the gut after a meal. Then, gut hormones involved in satiety will be released, reaching our circulation and informing the brain.
In conclusion, for the first time, this experimental study has shown a new sensory mechanism by which food in our gut is sensed by our brain, independently of gut hormones. Furthermore, the researchers emphasized in the discussion that this newly discovered pathway not only senses nutrients in the gut lumen, but also may be exploited by pathogens and will lead to new therapies for targeting conditions related to the gut-brain axis.
With the discovery of new “neuropod cells”, the study shows a closer relationship in terms of how the previously known neuronal and endocrine pathways communicate with nerves that carry sensory signals to the brain.
You can see a video from Duke University summarizing these novel findings here.
Kaelberer MM, Buchanan KL, Klein ME, et al. A gut-brain neural circuit for nutrient sensory transduction. Science. 2018; 361(6408):eaat5236. doi: 10.1126/science.aat5236.