Download PDF Spring Bridge on AI: Promises and Risks April 15, 2025 Volume 55 Issue 1 This issue of The Bridge features fresh perspectives on artificial intelligence’s promises and risks from thought leaders across industry and academia. Unlocking the Gut’s Brain with Ingestible Bioelectronics Friday, April 11, 2025 Author: Shriya Srinivasan Ingestible devices present a novel approach to accessing the gastrointestinal tract, making possible therapeutic interventions that can modulate gut function and potentially improve health outcomes. With the increasingly popular use of weight loss drugs, such as Ozempic and Wegovy (Sodhi et al. 2023), there has been a surge in the occurrence of gastroparesis, a gastrointestinal disorder wherein the stomach experiences paralysis, creating symptoms of nausea, vomiting, and abdominal pain. The prevalence and debilitating effects of gastroparesis have not only underscored that these drugs may not be the comprehensive solution we seek but have also raised the urgent need for us to rigorously understand such gastrointestinal disorders and develop effective treatments. At its core, this requires unraveling the intricate interactions between the gut and its nervous system—a relationship that is emerging as a significant frontier in medical research. The enteric nervous system (ENS), often called the gut’s brain, is a complex network of 400-600 million neurons embedded in the walls of the GI tract, running from the esophagus to the anal canal. As the largest and most complex part of the peripheral nervous system, it directs digestive processes and interacts with various organs to influence overall well-being. Researchers have uncovered that its complex functions among neural, hormonal, and microbial axes affect everything from mood and cognition to immunity and energy balance (Kaelberer et al. 2018). However, because of its highly interconnected nature with other organ systems, isolating its role has been challenging. Further, the intricate anatomy of the tract presents unique challenges in the design and engineering of devices that can interface with the ENS. Specifically, the nerves are embedded in a weblike pattern along the length of the gastrointestinal tract, which undergoes significant motion during peristalsis, the wave-like contraction of muscles lining the digestive tract. Ideally, we would be able to probe each segment of the tract (esophagus, stomach, intestines) and track its neural activity throughout the day, in response to activity, meals, diseases, and other variables, to understand the functioning of the ENS. Ingestible devices present a novel approach to access the gastrointestinal tract; with a form factor no larger than an everyday multivitamin, they allow us to record and stimulate the ENS at various points. This capability not only opens new research avenues but also paves the way for therapeutic interventions that can modulate gut function and potentially improve health outcomes. Given the unique properties of the GI tract, the design of an ingestible device requires creativity and a holistic approach. First, it must fit into a pill-sized form factor to be ingested orally and traverse the tract without causing obstruction or perforation. The surface of the device must withstand the pH of each segment and be resistant to the contents of the tract. Additionally, to effectively record and stimulate the ENS, devices must interact with the gut’s mucosal or muscular layers, anchoring themselves or having a robust contact mechanism. Finally, power and communication must be sufficiently miniaturized to be carried onboard or overcome the depth within the body to be wirelessly controlled by external devices. Early work on capsule endoscopy systems paved the way for the first ingestible devices, transforming our ability to visualize and diagnose GI tract conditions non-invasively (Iddan et al. 2000). These devices set design benchmarks in size and materials, crucial for safely navigating the harsh environment of the gastrointestinal tract. What neural interfacing capabilities can be achieved with ingestible devices? My research in Professor Giovanni Traverso’s lab at MIT delved into the possibilities from various angles to explore the challenges and potential of multimodal ingestible systems, specifically designed to interrogate the ENS. Chemical Actuation: Drugs, including serotonin and dopamine receptor agonists/antagonists, can directly modulate the ENS, which affects motility and the sensory functions, leading to nausea and vomiting. Evolving from dissolvable tablets and temperature-triggered materials to self-deploying needle systems for administering macromolecules directly into the gastrointestinal lining, the drug delivery field has seen dramatic advancements over the past few decades (Abramson et al. 2019). Incorporating mechanical and chemical elements, I recently developed the RoboCap. This ingestible utilizes an onboard motor to rotate miniature fins that clear mucus, similar to a tunnel-digging device, exposing the intestinal surface to allow the enhanced absorption of drugs, especially of large molecules (Srinivasan et al. 2022). These types of functionalities bolster the capability to deliver drugs in a targeted fashion and with controllable release kinetics. Electrical Actuation: ENS activation via stimulation has been previously achieved via unique geometries that prioritized high surface area contact with the lumen, the inner surface of the tract, or microneedle penetration into the muscle (Abramson et al. 2020; Ramadi et al. 2023; Srinivasan and Dosso et al. 2024). In conditions like ileus, intestinal paralysis, the entire tract must be stimulated. To achieve stimulation along the length of the intestines, my team and I designed the ingestible self-propelling device for intestinal reanimation (INSPIRE). This device opens up into an S-shaped device after reaching the intestines and performs electrical stimulation through four contacts at the edges, supported by an onboard power source and microcontroller. As the intestines contract in response to stimulation, the device undergoes a shape change and springs forward to stimulate the adjacent segment. By incorporating mechanical and electrical stimulation, this device improved intestinal motility by up to 140% and decreased mean passage time from 8.6 days in controls to 2.5 days. In addition to neuromuscular activation for motility, stimulating the ENS may allow us to modulate the neural pathways to trigger hormonal release. Mechanical Actuation: Another way to interact with the ENS is to trigger its mechanoreceptors with mechanical stimulation. In the case of obesity, I saw an interesting opportunity to tap into the hunger-satiety reflex circuit to harness the body’s own mechanisms to solve the issue of overeating. The vibratory ingestible bioelectronic stimulator (VIBES) is an ingestible device that vibrates the gastric musculature, artificially activating distension receptors. These artificially signal to the brain that the stomach is full— creating an illusory satiety. Swine treated with this pill felt early satiety and significantly decreased food intake (by roughly 40%). Interestingly, this also caused the release of hormones consistent with feeding (Srinivasan et al. 2023). By tapping into such neural reflex circuits, this device offers a mechanistic solution for obesity, which is also cost-effective, greatly increasing access to therapy. I envision a future in which ingestible devices will be able to monitor the tract and responsively stimulate it to allow for advanced insights and treatments for gastrointestinal health. Sensing: The ability to directly record from the ENS will be critical in improving our understanding and diagnosis of neural pathologies (Srinivasan and Liu et al. 2024). The multimodal electrophysiology via ingestible, gastric, untethered tracking (MiGUT) device rolls out a sensing electrode ribbon to make contact with the mucosa (You et al. 2024). The device then records and wirelessly transmits biopotentials to an external receiver. Similar embodiments extending these concepts to all segments of the GI tract will empower the development of analytical pipelines and electrophysiologic biomarkers for neurally mediated GI pathologies. Apart from electrical sensing, further research is required to develop robust mechanical, chemical, and molecular sensing strategies and to integrate these to provide a continuous readout of GI function along the tract. This would enable correlations between neural signals and disease states. Conclusion Wearable devices have fundamentally changed how we live. We can record our heart activity to curate workouts, granularly track our sleep to optimize restfulness, and even detect falls or warn us of noise levels. Similarly, I envision a future in which ingestible devices will be able to monitor the tract and responsively stimulate it to allow for advanced insights and treatments for gastrointestinal health. For example, in the context of gastroparesis, an ingestible device might reside in the stomach or intestines, continuously monitoring the pH of the contents along with the electrogastrogram (EGG), which provides electrical signals from the luminal surface. When the pH increases, as food enters the tract, if the EGG reflects depressed motility, then the device could electrically stimulate the tract to excite the ENS locally and promote peristalsis. Alternatively, a network of devices could also implement a responsive system and be able to coordinate function in the independent but linked segments of the tract. For example, devices monitoring the electrical activity of the intestines would survey for abnormal spasms and then deliver drugs at proximal and distal sites to reduce the unwanted muscular activity. We are still in the early days of development for such ingestible devices, but the future holds promise. The gut has been proposed as a crucial early biomarker for various diseases. As research in the microbiome and neuro-gastroenterology continues to expand, the potential of leveraging data from ingestible bioelectronics becomes increasingly compelling. These devices, designed to traverse the gastrointestinal tract, must meet rigorous engineering standards to withstand the challenging environment, maintain contact for effective monitoring and stimulation, and handle power and data transmission demands. Further, it is critical to address challenges relating to device disposal and environmental impact to ensure that sustainability considerations are sufficiently integrated into the development process. Ultimately, the future of ingestible bioelectronics will lie not only in their technological innovation but also in their potential to seamlessly integrate into and enhance existing medical practices and lifestyles. By advancing precision health monitoring and creating tailored therapeutic interventions, these devices offer a promising pathway toward significantly improving patients’ quality of life. References Abramson A, Caffarel-Salvador E, Khang M, Dellal D, Silverstein D, Gao Y, Frederiksen MR, Vegge A, Hubálek F, Water JJ, and 13 others. 2019. An ingestible self-orienting system for oral delivery of macromolecules. Science 363(6427):611–15. Abramson A, Dellal D, Kong YL, Zhou J, Gao Y, Collins J, Tamang S, Wainer J, McManus R, Hayward A, and 6 others. 2020. Ingestible transiently anchoring electronics for microstimulation and conductive signaling. Science Advances 6 (35):eaaz0127. Iddan G, Meron G, Glukhovsky A, Swain P. 2000. Wireless capsule endoscopy. Nature 405(6785):417. Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohórquez DV. 2018. A gut-brain neural circuit for nutrient sensory transduction. Science 361(6408):eaat5236. Ramadi KB, McRae JC, Selsing G, Su A, Fernandes R, Hickling M, Rios B, Babaee S, Min S, Gwynne D, and 8 others. 2023. Bioinspired, ingestible electroceutical capsules for hunger-regulating hormone modulation. Science Robotics 8(77):eade9676. Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. 2023. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA 330(18):1795–97. Srinivasan SS, Alshareef A, Hwang A, Byrne C, Kuosmanen J, Ishida K, Jenkins J, Liu S, Gierlach A, Madani WAM, and 3 others. 2023. A vibrating ingestible bioelectronic stimulator modulates gastric stretch receptors for illusory satiety. Science Advances 9(51):eadj3003. Srinivasan SS, Alshareef A, Hwang AV, Kang Z, Kuosmanen J, Ishida K, Jenkins J, Liu S, Madani WAM, Lennerz J, and 5 otheres. 2022. RoboCap: Robotic mucus-clearing capsule for enhanced drug delivery in the gastrointestinal tract. Science Robotics 7(70):eabp9066. Srinivasan SS, Dosso J, Huang H-W, Selsing G, Alshareef A, Kuosmanen J, Ishida K, Jenkins J, Madani WAM, Hayward A, and 1 other. 2024. An ingestible self-propelling device for intestinal reanimation. Science Robotics 9(87):eadh8170. Srinivasan SS, Liu S, Hotta R, Bhave S, Alshareef A, Ying B, Selsing G, Kuosmanen J, Ishida K, Jenkins J, and 5 others. 2024b. Luminal electrophysiological neuroprofiling system for gastrointestinal neuromuscular diseases. Device 2(7):100400. You SS, Gierlach A, Schmidt P, Selsing G, Moon I, Ishida K, Jenkins J, Madani WAM, Yang S-Y, Huang H-W, and 4 others. 2024. An ingestible device for gastric electrophysiology. Nature Electronics 7:497–508. About the Author:Shriya Srinivasan is an assistant professor of bioengineering at the Harvard School of Engineering and Applied Sciences and the director of the Harvard BIONICs lab, where she develops neurotechnology.