Research spanning many decades has shown nutrients in the gastrointestinal tract can shape animals’ flavor preferences. One of the earliest findings of this effect dates back to the 1960s, when Garvin Holman of the University of Washington reported hungry rats preferred consuming a liquid paired with food injected into the stomach rather than a solution coupled with a gastric infusion of water.
More recently Ivan de Araujo, a neuroscientist at the Icahn School of Medicine at Mount Sinai, and his colleagues have shown calories can trump palatability: Their work has demonstrated mice prefer consuming bitter solutions paired with a sugar infusion injected in the gut rather than a calorie-free sweet solution.
For years De Araujo and his group have been working to tease apart how the contents of the gut produce pleasure in the brain. In mice they have found sugar in the digestive tract can activate the brain’s reward centers. In animals bred without the ability to taste sweetness, sugary snacks still triggered activity in the ventral striatum, a brain region involved in reward processing. But according to De Araujo, the specific pathway that relayed signals between the gut and the brain remained a mystery.
Now, De Araujo and his colleagues have identified the vagus nerve, a bundle of fibers that connects the brain stem to the intestines and other major organs in the body, as a potential conduit of these gut-borne pleasure-related signals to the brain—at least in mice. Using optogenetics, a technique that involves genetically engineering animals so that flashes of light can activate specific cells, the researchers discovered stimulating neurons in the gut-innervating branches of the vagus nerve can induce the release of the neurotransmitter dopamine from the substantia nigra, a brain region involved in movement and reward.
The findings, which were recently published in Cell, also reveal animals would repeatedly poke their noses into holes in order to self-stimulate these cells—and that they preferred flavors paired with the activation of this circuit. “[Our study] provides a mechanism via which we understand why the presence of calories or nutrients in the gut changes our behavior,” De Araujo says.
Future studies will need to tease apart what types of gut stimuli, such as the presence of specific foods or the stomach stretch that occurs after a meal, will activate this pathway, notes Gary Schwartz, a neuroscientist at the Albert Einstein College of Medicine who was not involved with the work. “If one knew what kinds of stimuli we should give the gut to make [food] rewarding or not rewarding, maybe we can help control overeating or make people who don’t want to eat, eat more.”
Scientists have long known the gut–vagus–brain pathway is responsible for producing feelings of fullness, but this new study—and other recent research—has started to uncover new roles for this system in higher-order brain functions, says Scott Kanoski, a neuroscientist at the University of Southern California who was not part of the research. Earlier this year, his team found this circuit also controls some memory functions. Selectively cutting the branches of the vagus that were connected to the gut, they discovered, impaired the animals’ ability to form memories about new objects or locations.
Of course, additional research is necessary to confirm this type of circuit exerts the same behavioral effects in humans. In the meantime vagal stimulation is already used to treat emotional and eating disorders such as depression and obesity. And there is a growing interest in using this technique as a therapy for anxiety disorders and a variety of additional conditions—even Alzheimer’s and related memory disorders, Kanoski says. “Understanding more about the biology of the system could have implications for future applications.”
A key question that remains about these gut–vagus–brain pathways is: How is information about gut contents relayed to the sensory branches of the vagus nerve? One possibility is the vagus senses hormones within the gut, De Araujo says. Another was outlined in a recent Science study in which Diego Bohórquez, a neuroscientist at Duke University, and his colleagues discovered that some enteroendocrine cells, which are found in the walls of the gastrointestinal tract, directly form synapses with the vagus nerves of mice. Introducing an environmental stimulus—in this case, sugar—into the gut could activate this circuit. Bohórquez—who was also a co-author in De Aruajo’s study—dubbed these synapse-forming gut cells “neuropods.”
In addition to transmitting information about nutrients in the gastrointestinal tract, these newly identified vagal circuits may also be involved in bacterial signaling from the gut to the brain, says John Cryan, a neuroscientist at University College Cork in Ireland who was not involved in either study.
A large body of research now provides support for findings that the microscopic organisms in our intestines can influence behavior and mental health—and some evidence already suggests the vagus is a possible route via which these effects occur. In a 2011 study Cryan and his colleagues demonstrated that severing the vagus nerves of mice blocked the anxiety-reducing effects of the probiotic bacterium Lactobacillus rhamnosus. This study showed the vagus is critical for signaling to the brain by certain strains of bacteria. But how microbes send signals to the vagus remains an open question.
“It would be interesting to see if metabolites from the microbiome could activate these neuropod cells [or the] reward pathway,” Cryan says. “I think this is really exciting for the microbiome field.”