From Gut to Brain: How Serotonin and the Vagus Nerve Shape Our Mood and Health

Did you know that over 90% of your body’s serotonin is made in your gut—not your brain? And that your gut and brain communicate through a literal nerve superhighway? Welcome to the science of the gut–brain axis.

In recent years, scientists have begun to untangle one of the most fascinating communication systems in the human body: the gut–brain axis. This bidirectional network connects your digestive system and brain, with the vagus nerve as its main messenger and serotonin as a key chemical translator. A new review published in the International Journal of Molecular Sciences (2025) explores how this dynamic duo—the vagus nerve and serotonin—work together to regulate not just digestion but mood, stress, inflammation, and chronic illness.

The vagus nerve, Latin for “wandering,” is the longest cranial nerve in your body. It originates from the brainstem and travels down to your heart, lungs, liver, and gut. This nerve transmits up to 90% of its signals from the gut to the brain, not the other way around. These sensory signals inform the brain about the state of your digestive system—whether you’re hungry, full, inflamed, or stressed—and influence emotional and physiological responses. Notably, vagus nerve stimulation (VNS) has been shown to reduce depressive symptoms in patients with treatment-resistant depression.

Serotonin, often called the “mood molecule,” is widely associated with brain function. But the surprising truth is that the vast majority of serotonin is actually made in the gut, specifically by specialized cells in the intestinal lining called enterochromaffin cells. These cells convert dietary tryptophan into serotonin using enzymes such as TPH1. Once produced, serotonin activates vagus nerve endings, sending chemical messages to the brain that influence mood, immune response, and digestion.

What’s even more fascinating is that gut bacteria—your microbiome—play a critical role in this process. Friendly bacteria like Lactobacillus and Bifidobacterium ferment dietary fibers into short-chain fatty acids (SCFAs), such as butyrate. These SCFAs enhance serotonin production by stimulating TPH1, modulate the sensitivity of vagal nerve endings, and influence serotonin receptors. This means that a healthy microbiome doesn't just support digestion—it may also support better mood and mental resilience.

Once serotonin is released in the gut, it binds to specific receptors on the vagus nerve. These signals travel to the nucleus tractus solitarius (NTS), a processing center in the brainstem, which relays messages to higher brain regions like the dorsal raphe nucleus (DRN) and the locus coeruleus (LC). These areas regulate mood, attention, stress responses, and inflammation. This creates a serotonin–vagus–brain loop that influences emotional regulation, immune health, and autonomic balance.

When this system is dysregulated, it can contribute to a range of health issues. Low serotonin and altered vagal tone are common in conditions such as depression, anxiety, irritable bowel syndrome (IBS), and inflammatory diseases. For example, in IBS, excess serotonin from gut cells may over-activate sensory neurons, increasing pain and emotional sensitivity. Similarly, chronic inflammation can deplete tryptophan and reduce serotonin availability, contributing to mood disorders.

Fortunately, emerging therapies are beginning to address these root causes. Specific probiotics have shown promise in clinical trials for improving depression symptoms. Vagus nerve stimulation is already approved for some forms of depression. Dietary interventions that support SCFA-producing bacteria—such as fiber-rich whole foods—may help regulate serotonin naturally.

Looking ahead, scientists are developing more precise ways to map the gut–brain network using multi-omics technologies, brain imaging, and bioengineering. Future treatments may include microbiome-tailored antidepressants, personalized nutrition plans based on individual serotonin profiles, and targeted postbiotic therapies that influence the vagus nerve.

The old saying “gut feeling” is more than just a metaphor. Your belly isn’t just digesting food—it’s in constant dialogue with your brain, and serotonin is a big part of that conversation. Understanding this connection could transform how we approach everything from depression and anxiety to digestive health and chronic inflammation.

So take care of your gut—your brain is listening.

Based on: “Interaction of the Vagus Nerve and Serotonin in the Gut–Brain Axis” by Young Keun Hwang and Jae Sang Oh, published in the International Journal of Molecular Sciences, 2025.