PROJECT SUMMARY / ABSTRACT There are approximately 25 million Americans that suffer from Type 2 diabetes. Furthermore, about 35 million Americans >20 years old are diagnosed with prediabetes. More than one-third of Americans are also obese, an incidence that has nearly tripled from 1960 to 2010. Recent studies have shown that the gut-brain axis places a critical role in digestive and metabolic diseases. Further, direct communication between the sensory neurons in the gut and neural reward circuits in the brain plays a crucial role in detecting chemical cues such as hormones, satiety signals, or small molecule metabolites produced by bacteria in the gut. Chemicals in the small intestine are detected by specialized epithelial cells that transduce chemical signals into neuronal activity that can be interpreted by the central nervous system. An ingestible device that supersedes chemical cues and stimulates sensory neurons directly using electronic pulses could mimic the chemical milieu in the gut that is associated with healthy metabolic and digestive states. Spatiotemporal control of intraluminal sensory nerve stimulation in the gut could with help us understand the link between chemical signaling in the digestive system and neural circuits in the brain that are modulated by the gut-brain axis. Here we propose an ingestible electronic device with flexible electrodes that can pace sensory nerve activity in the gut of a pig model. Physiological responses will be measured, and brain activity will be monitored using fMRI. Initially, this project will validate this proof-of-concept using tethered electrodes in porcine subjects. Specifically, sensory neurons in the gut will be paced using biomimetic waveforms that will simulate fed or fasted states in porcine subjects while brain activity will be measured simultaneously using fMRI. These results will help us understand the connection between gustatory signaling, sensory nerve activity, and neural reward circuits in the brain such as satiety. In the future, we will design a fully autonomous smart pill with an on-board power supply and circuitry that selectively and non-invasively stimulate or block the activity of sensory neurons in the gut of human subjects. If successfully, this smart pill could serve as a low-risk device-based approach to help understand and potentially treat digestive and metabolic disorders of the gut-brain axis such as obesity and diabetes.

PROJECT NARRATIVE This project will design an ingestible electronic device that can non-invasively modulate the activity of sensory neurons in the gut. Using pig models, ingestible device with flexible electrodes will pace nerves that innervate the gut while brain activity will be recorded using fMRI. If successful, ingestible devices that modulate the gut- brain axis can serve as a platform technology to better understand and treat digestive and metabolic diseases including obesity and diabetes.