A patient told me last spring that she had stopped trusting her own body. Since recovering from a bad COVID infection she felt her heart race when she stood up, her digestion had turned unpredictable, and the steady background sense of being at home in herself was gone. She used a phrase I hear often: "I just don't have a gut feeling about anything anymore." She meant it as a figure of speech. I heard it as a clinical lead.
Our language gave away what physiology took two centuries to confirm. We get butterflies in the stomach before we speak in public. Bad news lands as a punch to the gut. We make a decision because something in our gut tells us to. These are not metaphors that happen to involve the abdomen. They are reports from a sensory system most people never knew they had, and the cable that carries them is the vagus nerve.
The Brain's Quietest Major Nerve
The vagus is the tenth cranial nerve, and it wanders from the brainstem down through the neck and chest into nearly every organ below it, the heart and lungs and the full length of the gut. People tend to picture it as a command line, the brain barking orders downward. The traffic mostly runs the other way. Somewhere around four-fifths of vagal fibers are afferent, meaning they carry information up to the brain rather than commands down to the body. Your gut is talking to your brain far more than your brain is talking back.
That upward stream is the physical basis of interoception, the sense of your own internal state. The vagus reports on stretch in the stomach wall, on the chemistry of what you've eaten, on the activity of trillions of resident bacteria. The brain integrates that signal into mood, appetite, and the felt sense of safety or threat. When the line is clean, you get an accurate gut feeling. When it's inflamed or degraded, the readout drifts, and people describe exactly what my patient did: a body they no longer quite trust.
When the Cable Gets Damaged
The clearest recent proof that vagal integrity matters came out of the COVID pandemic. A team publishing in Acta Neuropathologica in 2023 examined the vagus nerves of patients who died of COVID-19 and found SARS-CoV-2 RNA sitting in the nerve itself, alongside inflammation involving neurons, endothelial cells, and the Schwann cells that insulate the fibers. The inflammatory load tracked with the amount of virus present. In a cohort of more than 300 patients, the authors linked this vagal inflammation to autonomic dysfunction, and proposed it as a mechanism behind the dysautonomia that haunts long COVID.
That reframes a lot of cases I see. The racing heart on standing, the unreliable digestion, the fatigue and brain fog that follow a viral illness are often filed under anxiety. They look, mechanically, like an injured sensory nerve sending noisy signals to a brain doing its best to interpret them. This is the same territory we covered when writing about why POTS and ME/CFS are neuroimmune diseases, not anxiety disorders. The vagus is where a lot of that story is written.
Stress, the Gut Wall, and What the Vagus Drives
Damage is one failure mode. Chronic overdrive is another. Prolonged stress raises what researchers call allostatic load, the cumulative wear of a stress response that never fully switches off, and the gut absorbs much of it. Stress hormones change intestinal motility, loosen the gut barrier, and shift the microbiome toward dysbiosis, with measurable losses in the short-chain-fatty-acid producers that keep the intestinal lining healthy. The vagus sits in the middle of this, both reading the disturbed gut and helping drive the motility changes that disturb it further.
Based on my clinical experience, I have a strong suspicion that stress can contribute to the development of diverticulitis or colitis. The firmest published data connects diverticular disease to mood, not the other way around: a German cohort of more than 61,000 patients found that people diagnosed with diverticular disease went on to develop depression at notably higher rates over the following five years. The reverse direction, that high allostatic load raises the risk of diverticulitis itself, is biologically plausible through vagal efferent overdrive and a stressed microbiome, but it is still an emerging hypothesis rather than settled fact. I think it will hold up. The mechanism overlaps with what we described in our piece on depression as a brain energy crisis tied to the gut microbiome, and it rhymes with the bacterial-trigger story behind the gut bacteria that appear to trigger MS. The gut is not downstream of the brain. They are one circuit.
Why GLP-1 Drugs Keep Surprising Us
The class of medications everyone knows as weight-loss drugs, the GLP-1 receptor agonists like semaglutide, turns out to be a gut-brain drug first and a metabolic drug second. GLP-1 is a hormone released by the gut after eating; the receptors these drugs activate sit densely in the hypothalamus and brainstem and along vagal pathways. That anatomy explains why their effects reach so far past the waistline.
Two threads interest me clinically. First, in the hypothalamus, the neurons that regulate appetite and energy balance suffer a specific kind of cellular strain under chronic overnutrition called endoplasmic reticulum stress, which contributes to leptin resistance and a kind of metabolic exhaustion in those circuits. GLP-1 receptor activation appears to quiet that ER stress, which may be part of how these drugs let an overdriven hypothalamus recover rather than simply suppressing hunger. Second, GLP-1 agonism reduces neuroinflammation and oxidative damage broadly enough that semaglutide earned European approval in September 2025 as a stroke-management therapy, and trials in neurodegenerative disease are underway. We've written before about the Ozempic effect on the craving brain and the Lancet trial where semaglutide cut heavy drinking by 41 percent. A drug that calms vagal and hypothalamic signaling reducing the urge to drink is not a coincidence. It is the gut-brain axis doing exactly what the anatomy predicts.
What This Means for You
The practical lesson is that you can feel this system, and that the feeling is data. Patients who come through our Intensive Brain Health Program for IV NAD+ infusions often report something striking during the drip: a heightened, almost loud awareness of the gut-brain connection, a sense of their digestion and mood and breathing suddenly speaking in the same voice. I take those reports seriously. Interoception is trainable, and a clearer signal from a healthier vagus tends to show up as steadier mood, better appetite regulation, and the return of that trustworthy gut sense.
If your gut feelings have gone quiet or unreliable after an illness, a stretch of relentless stress, or years of metabolic strain, that is worth investigating rather than dismissing. The vagus nerve is the most direct line your brain has to the rest of you. When it speaks, the right move is to find out why, not to talk yourself out of listening.
Dr. Sean C. Orr, M.D., is a fellowship-trained neurologist and co-founder of The Neurogenesis Project.