The appetite-stimulating hormone ghrelin is released by endocrine cells in the stomach that are part of the enteric nervous system, which controls hunger, nausea, and feelings of fullness.

A team of investigators—with inspiration from a desert-dwelling, spike-covered lizard—developed an innovative ingestible “electroceutical” capsule that can modulate levels of the hunger-related hormone ghrelin in pigs. Their study results showed that when ingested, the electronic FLASH device can alter blood levels of the gastrointestinal hormone through electrical stimulation of the stomach, with potential applications in disorders including cachexia, eating disorders, and conditions that result in chronic vomiting.

The team says the new system has potential applications for treating gastrointestinal, neuropsychiatric, and metabolic disorders, including disorders that involve nausea or loss of appetite, such as cachexia, which is the loss of body mass that can occur in patients with cancer or other chronic diseases. The technology could also feasibly be adapted to deliver electrical stimulation to other parts of the GI tract.

“An ingestible pill that contains electronics instead of chemicals or drugs is very promising,” said Khalil Ramadi, PhD, an assistant professor at New York University and a research affiliate at Brigham and Women’s Hospital. “It provides a way to deliver targeted electrical pulses to specific cells in the gut in a way that can regulate levels of neural hormones in the body.” Added Giovanni Traverso, PhD, an associate professor of mechanical engineering at MIT, and a gastroenterologist at Brigham and Women’s Hospital, “We show one example of how we’re able to engage with the stomach mucosa and release hormones, and we anticipate that this could be used in other sites in the GI tract that we haven’t explored here. This study helps establish electrical stimulation by ingestible electroceuticals as a mode of triggering hormone release via the GI tract.”

Traverso is senior author, and Ramadi co-first author, of the team’s published study, titled “Bioinspired, ingestible electroceutical capsules for hunger-regulating hormone modulation,” in which they concluded, “We anticipate that this device could be used to treat metabolic, GI, and neuropsychiatric disorders noninvasively with minimal off-target effects.”

The enteric nervous system controls all aspects of digestion, including the movement of food through the GI tract. “The extensive enteric nervous system (ENS), which controls the function of the gastrointestinal (GI) tract, is an important component of the gut-brain axis,” the authors wrote.

Gastroparesis is a disorder that slows or stops the movement of food from the stomach to the small intestine, and gastric electrical stimulation (GES) is one of the few commercially established GI electroceutical interventions and is FDA-approved for gastroparesis under a Humanitarian Device Exemption, they explained. “GES systems are similar to a cardiac pacemaker and are used to treat gastroparesis by applying short-pulse, high-frequency (0.3 ms, 14 Hz) electrical impulses.” The team had previously observed that patients with gastroparesis who received these gastric pacemakers seemed to feel better in a manner disproportionate to the improvements in motility.

“Studies have repeatedly shown that gastric emptying time is not reduced in patients with implanted GES systems. These patients do, however, experience a notable reduction in symptoms, including nausea and vomiting. This observation led the researchers to investigate if the electrical stimulation was inducing a neurohormonal effect. “… we hypothesized that GES likely exerts a neuromodulatory effect on the gut-brain axis, specifically on the chemoreceptor trigger zone …” they noted. “We posited that this neuromodulation is achieved at least in part using direct neuronal excitation via stomach-brain vagal afferent pathways, hormonal modulation, or both.”

To test that hypothesis, the researchers used an electrical probe to deliver electrical stimulation into the stomachs of animals. They found that after 20 minutes of stimulation, ghrelin levels in the bloodstream were considerably elevated. They also found that electrical stimulation did not lead to any significant inflammation or other adverse effects.

Once they established that electrical stimulation was provoking ghrelin release, the researchers set out to see if they could achieve the same thing using a device that could be swallowed and temporarily reside in the stomach.

With further investigation, the team found that the response was mediated by the vagus nerve, the body’s longest autonomic nervous system nerve that connects the brain and gut. Once they established that electrical stimulation was provoking ghrelin release, the researchers wanted to see if they could achieve the same ghrelin release using a device that could be swallowed, and temporarily reside in the stomach.

They set out to create an ingestible capsule—an electroceutical—that could emit electronic signals and move through the body, eventually being excreted. Electroceuticals are devices that use electric signals to treat various conditions. Inside the device are battery-powered electronics that produce an electric current that flows across electrodes on the surface of the capsule. In the prototype used in this study, the current runs constantly but, the scientists noted, future versions could be designed so that the current can be wirelessly turned on and off.

One of the main challenges in designing such a device is ensuring that the electrodes on the capsule can contact the stomach tissue. The fluid in the stomach that coats the tissues can interfere with an electroceutical system, so the investigators also looked to nature for ways to wick away fluid and allow the system to still have good contact with stomach tissue.

To create a drier surface with which the electrodes can interact, the researchers took inspiration from the Australian lizard Moloch horridus, also known as the thorny devil. This animal’s fluid-wicking skin has ridged scales that allow it to better absorb water in the arid regions where it lives. When the lizard touches water with any part of its skin, water is transported by capillary action along the channels to the lizard’s mouth.

The team mimicked this lizard skin feature in the creation of their capsule design. The capsule surface consists of grooves with a hydrophilic coating. These grooves function as channels that draw fluid away from the stomach tissue. “Recognizing the challenges associated with electrical stimulation in the presence of gastric fluid and inspired by the water-wicking skin of Moloch horridus, the Australian thorny devil lizard, we developed a fluid-wicking capsule coating, which enables robust electrode-mucosa contact despite the persistent presence of gastric juice,” the scientists stated.

“We were inspired by that to incorporate surface textures and patterns onto the outside of this capsule,” said co-first author James McRae, a PhD candidate at the Massachusetts Institute of Technology’s department of mechanical engineering. “That surface can manage the fluid that could potentially prevent the electrodes from touching the tissue in the stomach, so it can reliably deliver electrical stimulation.”

The researchers tested their capsule by administering it into the stomachs of large animals. They found that the FLASH technology, which folds up electronics and a battery source inside of the capsule, was shown to reproducibly increase levels of ghrelin in pigs, resulting in a substantial spike in ghrelin levels in the bloodstream. “Although this effect is less than that seen with endoscopic stimulation, nevertheless, reliable increases in plasma ghrelin were observed,”  they stated.

The researchers also demonstrated that in order for this stimulation to work, the vagus nerve, which controls digestion, must be intact. “We also report the unexpected finding that, although ghrelin is a hormone released by gastric cells, GES only induces an increase in plasma ghrelin levels while the vagus nerve is intact.” They theorize that the electrical pulses transmit to the brain via the vagus nerve, which then stimulates endocrine cells in the stomach to produce ghrelin. “This suggests that GES activates a vagal reflex that then regulates ghrelin production,” they noted.

Ramadi commented, “As far as we know, this is the first example of using electrical stimuli through an ingestible device to increase endogenous levels of hormones in the body, like ghrelin. And so, it has this effect of utilizing the body’s own systems rather than introducing external agents.”  Traverso added, “The potential to modulate hormones using ingestible electroceuticals is potentially transformative because it does not require new drugs. Instead, it works alongside our physiological systems for the benefit of the person.”

Traverso’s lab now plans to explore using this approach in other parts of the GI tract, and the researchers hope to test the device in human patients within the next three years. If developed for use in human patients, this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with cachexia or anorexia, the researchers say. “It’s a relatively simple device, so we believe it’s something that we can get into humans on a relatively quick time scale,” Traverso noted.

McRae added, “This development provides many new avenues for research into the complex interconnections between the brain and gut and for furthering the use of electroceuticals as a clinical intervention.”

The authors further concluded, “Future ingestible electroceutical systems could be designed and customized for specific applications beyond acute, short-term gastric stimulation … FLASH is a platform to inform ingestible electroceutical development that could potentially be used for certain GI, neuropsychiatric, and metabolic disorders.”

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