Gut Health and Anxiety: When the First Brain Turns Up Pain and Worry

Gut health and anxiety are linked through inflammation and the gut lining itself. In mice, switching on the cells in the gut lining that release serotonin did two things. It made the gut overly sensitive to stretch. It also made the mice act anxious. So the bloated bowel, the worry and the pain that rides with both belong in one folder, not three.

Anxiety that shows up with a bloated, unpredictable bowel usually gets filed as two problems. The gut goes to one specialist, the worry to another. The pain that rides with both goes to a third. The evidence on gut health and anxiety says those three files belong in one folder.

In the video Your Anxiety Is a Fire in Your Gut, I, Dr. Gurpreet Singh Padda, MD, MBA, MHP, tell the story of one patient who lived inside that split for nine years. Here I go further into what a pain practice sees every day. How can an inflamed first brain sharpen gut pain? Why do some people feel the fire and others do not? And what actually moved symptoms when it was tested?

Nine years, two specialists and one missed pattern

She was in her forties when she came to see me. She took a serotonin reuptake inhibitor, first for panic. The dose had been raised twice for depression. It had never quite worked. In the same decade she lived with loose stools. Her bloating changed what she could wear by evening. She got an irritable bowel label only after everything else was ruled out. Her mood doctor never asked about her bowel. Her bowel doctor never asked about her mood.

Her labs told a story nobody had pieced together. Her C-reactive protein (a blood marker of inflammation) was 6.2. Her fasting insulin was high. She had taken three antibiotic courses in two years. Her diet had almost no fermentable fiber. That is not a careless-doctor story. It is what happens when medicine pays one bill for the skull and another for the bowel, and pays nobody to connect them.

The gut lining cell that can drive visceral pain and anxiety

The experiment that matters most for a pain patient here is one few people have heard of. In mice, researchers turned enterochromaffin cells up and down directly (Bayrer et al., 2023). These are the cells in the gut lining that release serotonin. Turning them on was enough to make the gut overly sensitive to stretch. It also made the mice act anxious. That settled once serotonin signaling was blocked.

Two details matter for chronic pain. Long activation left the gut oversensitive long afterward, even with no bout of inflammation to start it. The touchy nerve outlasted any fire. And in females, the circuit seemed to stay switched on all the time. This is mouse work, and brain serotonin was never measured. What it shows is a nerve made touchy from the lining. It is the same kind of process behind pain that no longer matches the scan.

For years I told patients a simpler version: the gut makes serotonin, so the gut runs your mood. The first half holds. The gut makes about 90 to 95 percent of the body’s serotonin. The second half does not. Serotonin cannot cross the blood-brain barrier (Chen et al., 2021). Gut serotonin runs gut movement, fluid release, clotting and immune signals. It reaches the brain as a message on a nerve, through 5-HT3 receptors on vagal fibers. It does not travel there in the blood.

Gut health and anxiety: same inflammation, different alarm

This fire can be lit on purpose. Give healthy adults a small dose of bacterial endotoxin (a piece of a germ’s outer wall), and their mood drops. One trial of one hundred and fifteen healthy adults looked for who dropped the most (Irwin et al., 2019). Three traits predicted it. One was the stress people already felt. One was how much it hurt them to feel left out. The third was the anxiety and low mood they already carried.

The striking part is what did not differ. None of those traits tracked how much the inflammatory chemicals rose. Everyone’s cytokines (immune alarm chemicals) climbed. What differed was how hard the alarm answered. In the people hit hardest, the inflammation switches inside cells were already firing harder at thirty minutes. That was before any cytokine had risen.

Chronic pain runs on the same rule. Two people can have the same damage on a scan and live totally different lives with it, because the amplifier is personal. Loneliness belongs on that list as a real body input, not a footnote. That is why social isolation behaves as an inflammatory state.

Hepatitis C clinics saw the real-world version for two decades. Some patients were treated with interferon, an inflammatory cytokine. Their risk of a major depression set off by the drug was higher with a past psychiatric disorder (OR 3.18). It was higher in women (OR 1.40). It was higher with more interleukin-6 at the start (Udina et al., 2012). The drug did not create the weak spot. It found it.

Only some patients are inflamed, and it shows in treatment

Inflammation is not the whole story of depression. Across 30 studies, 27 percent of people with depression had a CRP above 3 mg/L (Osimo et al., 2019). An antibody that blocks TNF made no overall difference in depression that resisted treatment. But the result turned on CRP at the start. Above 5 mg/L, 62 percent responded against 33 percent on placebo. The groups were small, only 13 and 9 patients (Raison et al., 2013).

A pain practice knows that pattern. The inflamed patient is rarely inflamed only in mood. It is the patient with the high insulin, the growing waist, the upset bowel and the pain that has not responded. That is why high insulin belongs in a pain workup. Her CRP of 6.2 put her right in that group. The wall that lets the fire start is its own subject, covered in the leaking gut wall.

Your medication list shapes your gut bacteria too

Drugs hit the gut far beyond antibiotics. One screen tested more than 1,000 drugs against 40 gut bacterial strains. Of the drugs made to act on human cells, 24 percent held back at least one strain. Antipsychotics showed up more than their share (Maier et al., 2018). In large population data, medication explained more of the differences in gut bacteria than any other factor measured (Falony et al., 2016).

It runs both ways. In depressed teenagers, several bacterial groups that had dropped came back after sertraline treatment. A pain patient on several daily drugs carries gut bacteria shaped partly by the pharmacy. That is not a reason to change any prescription on your own. It is a reason to hand the whole list to one physician who reads it as a system. That is where what else is in the pill picks up.

What moved symptoms: food before capsules

When treating the first brain was actually tested, food beat capsules. In the SMILES trial, adults with major depression were randomly assigned to diet coaching or social support. With diet coaching, 32.3 percent reached remission. With social support, 8.0 percent did. That means treating about 4.1 people with diet gets one extra remission (Jacka et al., 2017). In a head-to-head trial in stressed adults, a high-prebiotic diet cut mood problems (d = −0.60). A probiotic capsule fell short of that (d = −0.19). The two together did least (d = −0.03) (Freijy et al., 2023).

The body reason is specific. Gut bacteria ferment fiber into short-chain fatty acids. Butyrate, one of them, switches on the enzyme that enterochromaffin cells use to make serotonin (Hwang & Oh, 2025). In mice, acetate made from fermented inulin crosses into the brain. There it joins the brain’s own glutamate and GABA cycles. Fiber does not deliver a brain chemical. It changes how your own tissue behaves.

Inflammation then decides how much raw material the brain gets. Most free tryptophan in the blood gets used up down the kynurenine pathway. Inflammatory cytokines push more of it that way. The brain makes its serotonin from what is left over.

Where to start when pain, gut and mood travel together

• Ask whether your C-reactive protein has ever been measured. If it was above 3 mg/L, ask what explains it. One high value is a reason to repeat the test, not a diagnosis.
• Ask for a fasting insulin, not only a glucose.
• Bring every medication and supplement to a physician who reads them together.
• Build meals around fermentable fiber and whole foods. That is the input the trials tie to mood.
• Count conflict and loneliness as part of your medical history. They change how loudly the alarm answers.

None of this replaces the drug that steadies you. An antidepressant has a real job. Any change to it is a decision to work through with the physician who prescribed it. What it cannot do is put out a fire burning below the skull.

Some gene studies argue against this model. They do not settle it, and the full figures are laid out in the Deep Dive for Chapter 1, a companion to The Angry Gut, which I wrote with Ami Michelle Grimes. Have you not yet read why we call the gut the first brain? Begin with the enteric nervous system.

Frequently asked questions

Can gut problems cause anxiety?

They can add to it. In mice, switching on the cells in the gut lining that release serotonin made the mice act anxious. That settled when serotonin signaling was blocked. In people, signs of germ fragments leaking through the gut wall run higher in depression. The link is strongest in people with measurable inflammation. By CRP, that is about a quarter of depressed patients. See how we approach anxiety alongside chronic pain.

Does gut serotonin affect the brain?

Not directly. The gut makes around 90 to 95 percent of the body’s serotonin, but serotonin cannot cross the blood-brain barrier. Gut serotonin reaches the brain by firing vagal nerve fibers. Meanwhile, inflammation pushes tryptophan toward the kynurenine pathway. That leaves less for the brain to build its own serotonin. Follow the nerve that carries the signal.

Is chronic inflammation linked to depression?

In some people, yes. Across 30 studies, 27 percent of people with depression had a CRP above 3 mg/L, and 58 percent were above 1 mg/L. Setting off inflammation with endotoxin lowers mood in healthy volunteers. Interferon set off major depression in about one in four hepatitis C patients. The link is real but not universal. Read more on metabolic inflammation and depression.

Do probiotics help anxiety or depression?

The evidence is weaker than it is for food. Pooled probiotic trials in diagnosed patients show benefit. But the effect falls by nearly 32 percent once the weakest trials are removed, and certainty is rated low. In a direct test, a high-prebiotic diet beat a probiotic capsule on mood problems. See why a capsule is not a terrain strategy.

Should I stop my antidepressant if my gut is inflamed?

No. Gut inflammation is not a reason to stop or change a psychiatric drug on your own. The medicine steadies the receiver while the fire underneath gets treated. Changing it is a decision for you and the physician who prescribed it. Gut-directed care adds work the pill cannot do. Learn what else is in the pill you already take.

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Medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP, board certified in anesthesiology, pain medicine, interventional pain management, addiction medicine and obesity medicine. Adapted from Chapter 1 of The Angry Gut by Dr. Padda and Ami Michelle Grimes. Last reviewed September 2026.

Dr. Gurpreet Singh Padda, MD, MBA, MHP