The Quest for a Switch to Turn on Hunger

Maggie Chen

Let's face it, eating is pretty pleasant--snacking on a handful of crunchy chips or slurping down a large portion of stew, then lying on the couch in a haze of sated pleasure. But spare a thought for those who live in constant dread of mealtime. Eating, for some, is extremely painful. When your digestive system doesn't work as it should, nausea or vomiting can arrive after just a few bites. Or a badly digested meal can result in constipation, bloating, and lasting discomfort. Problems with digestion are far more common than you might think: Some 60-70 million people in the United States are thought to have some form of gastrointestinal disease.

One particularly uncomfortable condition is gastroparesis, where the passage of food through the stomach is dramatically slowed. It affects just under 2 percent of the US population, and its symptoms can be severe: decreased appetite, nausea, and vomiting. Most patients manage their condition with some form of dietary restriction, but in severe cases, invasive treatments are needed--involving tube feeding, implanted devices, or surgery. "It's a really needy area for which highly effective therapies do not exist," says Suneil Koliwad, an endocrinologist at UC San Francisco.

Researchers at the Massachusetts Institute of Technology have been working on a better solution. They've developed a tiny pill that, when swallowed, can send electric pulses through the stomach lining to get things moving. In research recently published in Science Robotics, the team showed that the pill raises levels of hormones that increase appetite and decrease nausea. They hope that it can one day act as an effective noninvasive therapy for those who experience gastroparesis--or other eating disorders--essentially being a temporary switch that can be activated to drive hunger and digestion.

The feeling of hunger and the passage of food is controlled by a smorgasbord of hormones and nerves inside the body, known as the gut-brain axis. "The gut has the second-largest number of neurons after the brain," says Khalil Ramadi, a bioengineer at New York University and one of the coauthors of the study. When this gut-brain axis is disrupted, whether by an eating disorder or diabetes, it is hypothesized that something like gastroparesis can result. To fix a digestive problem, this axis is where to focus.

So this is where the team started. One of the more invasive therapies for severe gastroparesis is called gastric electrical stimulation, where electrodes are surgically implanted under the skin of the abdomen to generate electric pulses into the stomach. Research in pigs has shown that this increases levels of ghrelin, a hormone associated with inducing hunger and reducing nausea. Giovanni Traverso, a mechanical engineer at MIT and the study leader, wondered if there was any way to make the therapy less invasive--minimizing any requirement for surgery.

Traverso, Ramadi, and the team decided to create something ingestible that could mimic the effects of gastric electrical stimulation. They settled on a capsule a few millimeters in size coated with a series of electrodes to generate electric pulses in the stomach once swallowed. By including a battery and a timer within the capsule, the little pill would send those electric pulses for a set time frame, then power down and pass through the rest of the digestive system, eventually ending up in the toilet.

Parth M.N.

Lauren Goode

Joel Khalili

Julian Chokkattu

Putting something electric into the wet and sticky environment of the stomach proved quite the design task. According to James McRae, a graduate student in Traverso's lab and another coauthor on the study, the electrodes needed to stick to the mucus lining of the stomach to successfully pass electric stimuli. The problem is that the mucus lining secretes large amounts of fluid, forming a layer that would typically hinder the electric conductivity.

To overcome this, the scientists turned to an unlikely source of inspiration: the Australian "thorny devil" lizard. This particular reptile has thorny grooves on its skin that wick away water--visually similar to the raised ridges on a Ruffles potato chip. Based on the lizard's textured skin, the scientists "incorporated grooves onto our capsule that can pull this layer on the mucosa away from the electrodes on the capsule," McRae says.

To make sure that the capsule wouldn't stick somewhere else on its way to the stomach and start pulsing before arriving at its destination, the scientists coated it with a protective shell that would melt away upon contact with fluid in the stomach. "Basically, that shell degrades, falls off, and exposes the electrodes and surface grooves to the appropriate region," McRae says.

To see if their tiny, grooved capsule actually worked, the team turned to pigs. After feeding each pig one pill, they tracked the capsule's passage using an endoscopic camera and radiography. They found that the pill did stick to the stomach, stimulating the mucus lining for around 20 minutes, and staying in the stomach for around one day. When the team measured ghrelin levels in the pigs' blood, they found that those that had ingested the electric pill had increased ghrelin in comparison to controls. "It was rewarding to see some positive results," Ramadi says with a smile.

Within two weeks, the scientists were able to collect the whole pills from the pigs' poop. This, McRae says, was "very encouraging safety data--that these devices can pass safely without causing harm, and that they can remain intact this whole time."

Interestingly, when they repeated this experiment in pigs that had a severed vagus nerve (disconnecting the gut from the brain), the pills' electrical stimulation didn't increase ghrelin--indicating that the brain played an important role in relaying hormone signaling in the stomach; the whole gut-brain axis was at work. "You're stimulating the stomach, and this hormone [ghrelin] is released by the stomach," Ramadi says. "But actually, there seems to be a neural involvement."

The fact that the pills can increase ghrelin is promising. However, further tests are needed to see if this leads to increased appetite or decreased nausea. "People can measure the ghrelin hormone and some of the biological changes," says Braden Kuo, a gastroenterologist at Brigham and Women's Hospital who was unaffiliated with the study (though Traverso previously studied as a clinical fellow under Kuo). "But I think it's still a long way off from proving that sort of manipulation can change human behavior."

Despite this, both Kuo and Koliwad agree that the pill is an advance into making gastroparesis treatment less invasive. Current implanted gastric electrical stimulators "put off a lot of patients who are fearful of undergoing the procedure," says Koliwad. This swallowable device "might be more palatable and acceptable to patients," he adds.

In the near future, Traverso, Ramadi, and McRae hope to push the pill into clinical trials. They envision the device as something that can one day target and stimulate different parts of the gastrointestinal tract--modulating hormones that can ease nausea or control appetite. This, they say, could be useful in a variety of disorders, such as nausea from chemotherapy, not just gastroparesis. "To me, as a clinician, the ability to enhance our hormone profiles without administering a drug is, I think, really transformational," Traverso says. "It has a tremendous opportunity to help across many areas."