It affects your mood, your sleep, even your motivation to exercise. There’s convincing evidence that it’s the starting point for Parkinson’s disease and could be responsible for long COVID’s cognitive effects. And it sits about 2 feet below your brain.

The gut plays an obvious role in our health by digesting what we eat and extracting nutrients. But there’s a growing appreciation among scientists that our digestive systems affect our general well-being in a much broader fashion. One fascinating aspect of the gut’s widespread impact on health is its direct influence on and communication with the brain, a conduit known as the gut-brain axis.

Through direct signals from the vagus nerve, which connects the brain and the gut, as well as through molecules secreted into the bloodstream from our gut microbes and immune cells that traffic from the gut to the rest of the body, our brains and our digestive tracts are in constant communication. And when that communication goes off the rails, diseases and disorders can result.

Gut feelings

The gut-brain connection is a key part of how the brain forms a picture of the rest of the body, a phenomenon known as interoception, explained Christoph Thaiss, PhD, an assistant professor of pathology at Stanford Medicine. In neuroscience, there’s a history of research on exteroception, how we understand the external world. We have a decent understanding of the five senses we use to perceive our surroundings and how those signals are transmitted from their external states (light photons, sound waves, flavor molecules) into electrical information in the brain.

But when it comes to our murky insides, science is much more in the dark. We don’t know how many senses are involved in interoception. Scientists still don’t have a good picture of sensory neuron anatomy in the body, which nerves connect to which tissues. And researchers are just starting to discover some of the molecules involved in internal sensation. What they do know is that many of these molecules originate in the gut, be they by-products of metabolism or secretions from the bacteria that reside in our intestines.

“These molecules are extremely important for the brain to make sense of what’s going on inside the body and then regulate physiological states accordingly,” Thaiss said.

Those physiological states include hunger, tiredness, a need to empty your bladder or states that don’t rise to conscious perception like maintaining your blood glucose levels.

The vagus nerve and long COVID

In collaboration with Stanford Medicine’s Maayan Levy, PhD, an assistant professor of pathology, Thaiss is exploring how impaired gut-brain signals during long COVID could cause cognitive problems, such as brain fog and memory lapses.

In a study published in 2023, the scientists found that long COVID is associated with a reduction in the body’s natural levels of serotonin, a signaling molecule that is produced the brain and the gut. In the brain, serotonin influences mood, sleep and memory. In the rest of the body, it plays a role in physiology, but Thaiss and Levy found that gut-produced serotonin can affect the brain as well.

In mice engineered to mimic human long COVID, activity of the vagus nerve was reduced. The animals also had memory and other cognitive deficits similar to those in humans with long COVID. When the scientists treated the mice with fluoxetine (Prozac), an antidepressant that raises levels of serotonin in the brain and body, the animals regained their full cognitive abilities.

Before these findings, scientists debated how SARS-CoV-2 could cause cognitive problems, as it is unclear if the virus breaches the blood-brain barrier. But the study by Thaiss and Levy suggests that the disease could have direct influence on the brain via the vagus nerve, regardless of whether the virus enters the brain. The researchers now want to investigate whether electrically activating the vagus nerve, a treatment that is Food and Drug Administration approved for conditions such as epilepsy and treatment-resistant depression, could alleviate long COVID’s cognitive symptoms.

“In the past, we thought that cognition or other features of brain activity only involved the brain proper,” Thaiss said. “Now we understand there are so many ways to influence the brain from the periphery, including from the gastrointestinal tract, and people are more and more thinking about using these peripheral tissues as a sort of remote control of brain function.”

The gut’s ecosystem

Much of the gut’s influence on the brain seems to be driven by the gut microbiome, the collection of (usually) beneficial bacteria and other microscopic organisms that reside in our digestive tracts. Introducing gut bacteria into germ-free mice has been shown to reduce anxious behaviors in the animals, and fecal transplants from humans with depression into rats ramped up depression and anxiety-like behaviors.

A study led by Thaiss, published in 2022, found that mice’s gut microbiomes influence their motivation to exercise. The team found that in a diverse population of mice, those that were more inclined to run on their exercise wheels had different microbiomes than their sedentary brethren. When the researchers performed a microbiome swap via fecal transplant, the animals’ exercise enthusiasm also switched. The scientists traced the difference to certain fatty acid metabolites generated by the microbes in exercise-loving mice; these molecules in turn stimulate nerves in the gut that send signals to the brain to produce dopamine, a brain hormone associated with pleasure.

A person’s mental health can also impact their gut health. Psychological stress has been shown to impact the makeup of the gut microbiome, either indirectly (stressed people may turn to comfort food-heavy diets which in turn change their microbiome makeups) or directly through molecular signals that travel from the brain to the gut and cause certain bacterial species to grow and divide and others to die back. Stress is often linked to “pro-inflammatory” bacterial species in the gut.

“There is a two-way street where our gut microbes can talk to our brain and our brain can talk to our gut microbes,” said Justin Sonnenburg, PhD, the Alex and Susie Algard Endowed Professorship and a professor of microbiology and immunology, who studies the gut microbiome. “Anyone who’s been stressed out and seen an effect on their gut motility has experienced this in a clear way.”

Although we’re not yet at the point to target improvements of the microbiome to specifically boost brain function, Sonnenburg said, we know how to keep our guts generally healthy. He led a 2021 study showing that feeding people a diet high in fermented food increased the healthy diversity of their gut microbiome and lowered their overall levels of inflammation. High-fiber diets have also been shown to support a healthy gut microbiome.

The seat of disease

The gut may also be the origin for some brain disorders. In Parkinson’s disease, a neurodegenerative condition that affects motor neurons in the brain, gut issues such as constipation and heartburn precede movement symptoms by years or even decades. Researchers have found differences in the gut microbiome in patients with Parkinson’s. And a 2024 study from Harvard researchers found that damage to the upper digestive tract, as with GERD or chronic ulcers, increases the risk of developing Parkinson’s disease years down the road.

Parkinson’s is characterized by clumps of a misfolded protein known as alpha-synuclein in the brain, similar to amyloid plaques that are a hallmark of Alzheimer’s disease. These protein clusters, known as Lewy bodies, may originate in the gut – studies have shown that the misfolded protein can traffic directly from the gut to the brain via the vagus nerve, and people whose vagus nerve has been severed (a rare surgical treatment for severe ulcers) have lowered risk of Parkinson’s. Certain bacterial species in our guts produce a protein very similar to misfolded alpha-synuclein, known as curli. Animal studies have found that curli can spur misfolding in alpha-synuclein, hinting that the disease could arise from dysfunction in the microbiome.

Stanford Medicine professor of hematology and genetics Ami Bhatt, MD, PhD, and professor of neurology Kathleen Poston, MD, are leading a project to study how the gut microbiome and immune system may interact to drive Parkinson’s disease. In Bhatt’s lab, researchers including Meena Chakraborty and Bianca Palushaj, MD, have collected stool and blood samples from more than 100 people with Parkinson’s and matched healthy controls, typically the partners or spouses of the patients. Comparing people who live in the same household will allow the researchers to focus on the disease’s impact on the microbiome and immune system, as many environmental differences will be eliminated.

Your second brain

The gut also contains the largest number of neurons outside the brain of any structure in the body – more than 100 million neurons line the human digestive tract, from the esophagus to the anus. These cells make up what is known as the enteric nervous system, which some scientists refer to as a “second brain.”

The enteric nervous system is more brain-like than other peripheral nerves because it consists of lots of different types of neurons that communicate with each other, while other peripheral nerves primarily serve to communicate between the brain and the body, said Julia Kaltschmidt, PhD, a Wu Tsai Neurosciences Institute Faculty Scholar, the Firmenich Next Generation Faculty Scholar, and an associate professor of neurosurgery. In fact, the gut’s nervous system can act alone.

Scientists have found that if they remove an animal’s gut and bathe it in a special fluid designed to keep neurons alive, the gut continues to contract, pushing its contents from top to bottom.

Kaltschmidt and her team have designed 3D-printed synthetic mouse fecal pellets to quantify the gut’s ability to move matter. They’re looking at how certain genes affect the patterning of gut neurons during embryonic development, as well as how the activity of these neurons affects the gut’s transit speed.

They found in a recent study that stimulating certain long neurons “that are really fabulous in their anatomy,” Kaltschmidt said, dramatically speeds the pellets’ movement through the disembodied guts. Kaltschmidt hopes to build on these findings to create a “pacemaker for the gut” to stimulate these nerves and alleviate chronic constipation that accompanies aging and certain diseases. 

“Eating and digesting is really at the core of being a freely moving and thinking organism, and we’re increasingly recognizing the importance of the enteric nervous system in this more general sense,” Kaltschmidt said. “This system not only keeps the gut working, but plays a central role in health and disease and perhaps even in our experience of the mind.”