Choosing what to eat hinges on a constellation of factors: The smell of freshly baked bread, the taste of a tomato, or the knowledge that a bowl of greens will do you good, can spark your brain to tell your body to take a bite.

However, in a new study on mice, researchers discover food choices depend on processes extending far beyond the brain. Instead, the gut and the brain communicate, forming a complex digestive-brain axis that shapes behavior and food preferences.

The new research was conducted in animals, not humans, but the results could inform how we understand factors driving food consumption, and lead to new ways to treat eating-related disorders like obesity, the scientists say. Even when mice never tasted a high-calorie food, they were compelled to seek it out, driven by nutrient signaling occurring deep within the gut.

"There are some characteristics of food, namely the calorie content, that produce sensory stimulation, even after food has been swallowed," Albino Oliveira-Maia, a neuropsychiatrist at the Champalimaud Foundation and co-author of the new study, tells Inverse.

Such stimulation, though seemingly more subtle than that from tasting and smelling, has a critical impact on feeding behaviors, the researcher explains.

These findings were published Monday in the journal Neuron.

From the mouth to the gut — Researchers have known for decades that food behavior is influenced by far more factors than taste alone. But just how influential communication from the gut, called post-ingestive nutrient sensing, is has been mysterious.

When you eat something, the first thing that happens is that the mouth decides whether the food should be accepted — or spit out. Once chewed, food is broken up into nutrients, and the post-ingestive phase begins.

"In this phase, it's the digestive system's turn to 'taste' the food and talk to the brain about your meal choice," Oliveira-Maia says.

The digestive system then shares key info with the brain: how nutritious a food is, how much should be eaten, and how and individual should respond to the same food in the future. This adaptive process is called post-ingestive learning.

Researchers discover a novel digestive-brain axis that shapes food choices. FernandesMaia 2020 Neuron

Researchers wanted to know if post-ingestive learning would drive animals to actively seek out certain types of food. They developed an experiment where mice pressed levers to receive a direct injection of food into their stomach. This direct injection bypassed the animals’ taste buds and eliminated the palatable aspects of food or how good or bad the food tasted, the researchers say.

One lever triggered the injection of high-calorie food (sucrose or table sugar) while the other triggered the injection of low-calorie food (sucrose, a zero-calorie artificial sweetener). Throughout the experiment, mice were free to press either lever, while the researchers documented their choices.

Initially, mice pressed each lever equally, but as time went on, they pressed the high-calorie lever much more frequently — even though they were not able to taste the food.

These results suggested that there was a form of post-ingestive learning that hadn't been pinpointed before: A relationship between the digestive system and brain that compels animals to seek out food they've never actually tasted.

Brain signaling — To pin down exactly what parts of the body were involved, the team tweaked the animals’ biological machinery and saw how they responded to the same task.

The team honed in on the vagus nerve, the longest cranial nerve that runs from the brain to the abdomen which communicates information from the liver to the brain. In turn, they realized that when they cut the liver-related branch of the vagus nerve, the mice didn't engage in this form of post-ingestive learning.

But where, exactly, were these post-ingestive signals being sent in the brain? The team hypothesized that dopamine — the “pleasure” neurotransmitters, which are concentrated in the ventral tegmental area (VTA) of the brain — was involved. The VTA plays an important role in the body's reward circuit, which drives behavior to satisfy our most basic needs: eating, reproducing; responding to aggression.

"Dopamine neurons have been shown to respond to reward, for example when a sweet treat reaches our tongue," Rui Costa, a co-author and researcher at Champalimaud Research, explains. "This study shows that these neurons are also activated when foods reach the stomach and intestine."

When nutrients reach the gut, dopamine neurons are activated, a shift that then drives food choices, Costa explains.

Taken together, these results suggest that dopamine neurons responded to post-ingestive signals and without dopamine activity, post-ingestive learning isn't possible.

A novel learning process revealed — The researchers also observed that mice's dopamine spiked more when they licked sucrose than when sucrose was injected, suggesting that oral signals from taste drive dopamine activity and initiate food behavior, independent of post-ingestive signals.

When the team tested whether dopamine neurons were influenced by the liver-related branch of the vagus nerve and eliminated this branch, the neuron's response to post-ingestive signals dropped. Without activated dopamine and the liver-related branch of the vagus nerve intact, the mice weren't able to detect what was the best food for them — the high-calorie, energy-dense sucrose versus the empty calorie artificial sweetener.

This learning process that links the gut and brain compels animals to seek out food that they never actually tasted — a discovery that underscores how much of food choices are out of conscious control. Some food companies may even be manipulating these gut signals to keep people coming back for more, Oliveira-Maia says.

"Many processed foods already have high levels of sugar or other simple carbohydrates and it is likely that this has an impact on decisions to eat such foods," Oliveira-Maya explains.

More research is needed to see how this complex process plays out in the human body, but Oliveira-Maia is hopeful that the simple knowledge of gut signaling will help attract people to healthier food.

"It's very early to say what will come from this work down the line," Oliveira-Maia says. "Still, the inspiration regarding the relationship between dopamine receptors and obesity is a big part of why we did this work in the first place."

Abstract: Postingestive nutrient sensing can induce food preferences. However, much less is known about the ability of postingestive signals to modulate food- seeking behaviors. Here we report a causal connection between postingestive sucrose sensing and vagus-mediated dopamine neuron activity in the ventral tegmental area (VTA), supporting food seeking. The activity of VTA dopamine neurons increases significantly after administration of intragastric sucrose, and deletion of the NMDA receptor in these neurons, which affects bursting and plasticity, abolishes lever pressing for postingestive sucrose delivery. Furthermore, lesions of the hepatic branch of the vagus nerve significantly impair postingestive-dependent VTA dopamine neuron activity and food seeking, whereas optogenetic stimulation of left vagus nerve neurons significantly increases VTA dopamine neuron activity. These data establish a necessary role of vagus-mediated dopamine neuron activity in postingestive-dependent food seeking, which is independent of taste signaling.