How Does Vagal Signaling Shape the Brain's Threat Response?

++Introduction ++

Anxiety and fear are emotional states that are activated by the coordinated complex activities of the brain, and for a long time, it was presumed to be coordinated by the brain only.
This paper tries to explore whether the gut amplifies or regulates the brain’s anxiety, fear, and threat response and to what degree it does so.
Recent studies show the involvement of the gut, wherein researchers are actively trying to understand how it influences such emotions and how the gut contributes towards them.
The anxiety and fear response in our body involves two major stress response systems: Rapid autonomic response — SAM system and a Slower neuroendocrine response — HPA axis.

However, the stress response is not solely limited to these pathways; the vagus nerve connecting the brain and the gut plays a vital role as well. This paper reviews the evidence from vagal deafferentation, gut infection, probiotic, and vagus nerve stimulation(VNS) studies to propose a model of when and how the gut contributes to threat reactivity.

++Background++

The brain receives the exteroception signals, which get relayed at the thalamus to the amygdala, which plays a major role in the detection and perception of the threat. The amygdala then activates the regions including the hypothalamus and brainstem, thereby generating both behavioral and physiological responses.  The activation of the hypothalamus stimulates the sympathetic–adrenomedullary (SAM) system, leading to a cascade of reactions that ultimately cause the rapid release of adrenaline and noradrenaline,
while the activation of the hypothalamic pituitary adrenal (HPA) axis produces a slower and more sustained cortisol response.

The vagus nerve running from the brain branches out to different organs and involves efferent and afferent fibers. This paper primarily focuses on the vagal afferent signaling to analyze the role of the gut in stress response systems .
Approximately 80% of the fibers in the vagus nerve are afferent, carrying sensory information from visceral organs, mainly the gastrointestinal tract, toward the brain.
The brain uses these signals to construct or regulate the key emotions of the human body.

++Evidence++

Several pieces of evidence from vagal deafferentation, gut infection, probiotics, and vagus nerve stimulation (VNS) have been correlated to draw a model of when and how the gut contributes to threat reactivity.

One of the early studies by Goehler, Lyte & Gaykema (2007) titled "Infection-induced viscerosensory signals from the gut enhance anxiety” discusses the results where the mice were given a live Campylobacter jejuni bacteria (a common cause of food poisoning) orally and it seemed to appear more anxious on the elevated plus maze assay than control mice.
There were no cytokines discovered in the blood and the mice did not show any classic sickness behavior.
Since the bacteria does not enter the blood and has only reached the gut, the gut must have communicated with the brain through the vagus nerve (since the enteric nervous system operates locally and does not directly signal to the brain, any gut-brain signal has to have happened via the vagal nerves).
This was further verified by checking of the c-Fos protein in the nodose ganglion. The c-Fos started appearing in vagal sensory neurons around 5 hours after infection, peaking at 7–8 hours, overlapping with the time it takes for the bacteria to reach the cecum and for the protein to switch on.
The mice were subjected to an open field/hole board test (an anxiety-provoking novel environment with 9 holes to explore).
The infected mice were found to be hugging the corners and avoiding the centre. This paper demonstrates that infection in the gut increases the anxiety level of the mice in an innate anxiety test assay.

The Klarer et al. (2014) study, "Gut Vagal Afferents Differentially Modulate Innate Anxiety and Learned Fear,” conducts a SDA (subdiaphragmatic vagal deafferentation) and subjects the rats to different assays to learn the relationship.
It was seen that the SDA rats showed a decrease in innate anxiety in the absence of afferent vagal signals, but showed increased impaired (slower) extinction in the learned fear assay.
The paper tries to map this opposite dissimilarity by referring to a complementary study: vagus nerve stimulation (VNS) where the stimulation of the vagus nerve speeds up the fear extinction and thereby drawing a correlation between by stating that more vagal afferent activity causes faster fear extinction and no vagal afferent activity causes slower/impaired fear extinction. Though it is crucial to note that VNS sends non-selective blunt signals that broadly activate the vagal fibers rather than the actual natural afferent signals produced by the gut. Thereby drawing a direct similarity correlation would not be ideal rather is more about the electrical activity output.

The Chu, Murdock et al. 2019 study, published in Nature, titled "The microbiota regulate neuronal function and fear extinction learning."
Shows how there is no change in fear extinction deficit in mice with depleted or absent gut microbiota (via antibiotics and germ-free rearing) after cutting the vagus nerve.
But instead it was found that four microbiota-derived metabolites were significantly reduced in the blood (serum) and cerebrospinal fluid of germ-free mice, along with altered prefrontal cortex gene expression and impaired synaptic remodeling. The authors propose that these circulating metabolites may be the route by which the fear-extinction learning is disrupted or delayed.

The Bravo et al., 2011 ( and Otsuki et al., 2026) study shows how a mouse on being administered L. rhamnosus (probiotic administration) showed an absence of calming effect when the vagus was surgically cut out, indicating the presence of an intact vagal pathway for the calming effect. 

A study using a gut inflammation (colitis) model representing dysbiosis found that vagal afferent signals reach the amygdala, the brain region responsible for threat detection and fear processing, relayed through the locus coeruleus (a brainstem region). This demonstrates that dysbiotic gut states, much like the beneficial signaling seen with probiotics, communicate to the brain via the vagus nerve and cause increased levels of anxiety.

++Discussion++

Taking all the studies together, it suggests that the vagus plays a crucial role in the gut-to-brain threat signaling whose involvement appears to depend on whether the gut contains an active bacterial presence or not rather than whether the presence is beneficial or harmful. The infected state, dysbiosis state, and probiotic administration showed that the presence of active bacteria, be it good or bad, had vagus-dependent effects. But the total absence of microbiota showed effects independent of vagus afferents.
This could possibly be due to the required presence of local physical/chemical changes, inflammation, bacterial metabolites, etc., meaning something must be present to detect. When bacteria are entirely absent, there's no local signal to sense, thereby having no local signals for vagal afferents to detect.
A further asymmetry seen across the reviewed studies worth noting is that most of the vagal pathway evidences (Goehler et al., 2007; Klarer et al., 2014; Bravo et al., 2011; Chen et al., 2023) establish that the presence or absence of vagal signaling alter the response state without directly measuring the metabolites involved . Chu et al. (2019) is the exception that identifies four candidate metabolites depleted in germ free mice and links their absence to impaired synaptic remodeling in the prefrontal cortex.
This synthesis has translational relevance ie Irritable Bowel Disorder patients show a 3 to 6x increased risk of anxiety disorders (Chen et al., 2023). Meanwhile, VNS is already an approved treatment for depression and epilepsy and is being investigated for PTSD which could be implied from the above studies .Understanding how these vagal signals travel and are interpreted , we can infer how they could translate in a clinical setting.

++Limitations++

This review has several limitations. No study which has been reviewed here quantifies the gut's precise contribution to threat response, so its overall gravity in the fear/anxiety response remains unclear. Making it more qualitative than quantitative.
Nearly all evidence comes from rodent models, and direct translation to human threat processing has not been tested.
Additionally, whether infection-induced anxiety involves changes in the same gut bacteria-derived metabolites implicated in germ-free mice remains unexplored, since the infection study did not measure metabolite levels. Different gut states ie dysbiosis, infection, absence, use different behavioral measures, thereby making direct comparisons between them non-ideal.
Also, this synthesis is based on a small number of studies and should be treated as a preliminary model rather than a definitive account.

++Conclusion++

This review indicates that the gut makes a genuine contribution to the brain's threat response system and not as a one-directional, brain-driven process, but rather a bidirectional feedback loop between the gut and brain. The nature of this contribution depends on the state of the gut ie whether the bacteria are present (beneficial, harmful, or dysbiotic) or entirely absent, which determines whether the vagus nerve or systemic pathways carry the signal. Future work could explore these questions in more detail, including how strongly the gut contributes relative to other systems and to what degree, and how the different gut states and their responses discussed here might be compared more directly when done using comparable studies.

++References++

1. Goehler LE, Lyte M, Gaykema RPA. Infection-induced viscerosensory signals from the gut enhance anxiety. Brain Behav Immun. 2007;21(6):721–726.

2. Klarer M, Arnold M, Günther L, Winter C, Langhans W, Meyer U. Gut vagal afferents differentially modulate innate anxiety and learned fear. J Neurosci. 2014;34(21):7067–7076.

3. Otsuki T, Ichiki T, Terunuma M. Gut-to-brain interoceptive pathways in emotion-related behaviors. Front Syst Neurosci. 2026;20:1855213.

4. Chu C, Murdock MH, Jing D, et al. The microbiota regulate neuronal function and fear extinction learning. Nature. 2019;574(7779):543–548.

5. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus rhamnosus strain regulates emotional behavior and central GABA receptor expression via the vagus nerve. PNAS. 2011;108(38):16050–16055.

6. Chen CH, Tsai TC, Wu YJ, Hsu KS. Gastric vagal afferent signaling to the basolateral amygdala mediates anxiety-like behaviors in experimental colitis mice. JCI Insight. 2023;8(12):e161874.