How Do the Gut and Brain Communicate? – Understanding the Gut-Brain Axis

Stress can affect the gut – but the gut can also send signals back to the brain. New research shows how nerve signals, the immune system, the intestinal barrier and substances produced by bacteria can together contribute to communication between the gut and the brain.

Have you ever felt nervous and at the same time experienced stomach pain, bloating or a sudden urge to go to the toilet? This is a clear example of how the brain can affect the gut.

But communication also works in the other direction.

What we call the gut-brain axis is a bidirectional communication system in which the brain affects the gut while information from the gut is continuously sent back to the brain.

New research has made this communication particularly interesting. The focus is no longer only on which bacteria are present in the gut, but also on where the bacteria are located, which substances they produce and how well the intestinal barrier functions.

Three factors are particularly interesting here:

Stress, small intestinal bacterial overgrowth (SIBO) and increased intestinal permeability – sometimes referred to as “leaky gut”.

The Gut and Brain Communicate in Several Ways

The gut and brain communicate with each other through several parallel systems:

• The nervous system, particularly the vagus nerve and the enteric nervous system.
• The immune system, including cytokines and other inflammatory signals.
• The hormonal and stress systems, including the HPA axis and cortisol.
• The bloodstream, which can transport bacteria-produced metabolites and other molecules from the gut to other parts of the body.

This means that changes in the gut can potentially be detected by the brain in several different ways at the same time.

The Vagus Nerve – A Communication Pathway from the Gut to the Brain

The vagus nerve is one of the body’s most important communication pathways between the internal organs and the brain.

It is easy to think of the vagus nerve primarily as a nerve that controls the gut from the brain. Anatomically, however, the opposite is closer to the truth:

Approximately 80% of the vagus nerve’s fibers are afferent and carry sensory information from the body’s internal organs towards the brain, while approximately 20% are efferent and carry signals from the brain towards peripheral organs.

The gut is therefore not only a recipient of information from the brain. It is also an important source of information reaching the brain.

Vagal nerve endings can be indirectly influenced by, for example, nutrients, hormones, immune signals and substances produced through bacterial metabolism.

Stress: When Communication Travels from the Brain to the Gut

Stress clearly illustrates the opposite direction of communication within the gut-brain axis.

When we experience stress, the sympathetic nervous system and the body’s HPA axis are activated, among other responses. Stress hormones such as cortisol and catecholamines alter the body’s physiology to help us deal with the situation.

In the gastrointestinal tract, prolonged or intense stress can affect, among other things:

• gut motility
• secretion
• the immune system
• mast cells
• the microbial environment
• intestinal barrier function

In some people, stress may therefore contribute to gastrointestinal symptoms such as bloating, diarrhoea, constipation and abdominal pain.

Can Stress Contribute to Leaky Gut?

The inside of the intestine is covered by a thin layer of epithelial cells that forms a barrier between the contents of the gut and the rest of the body.

Between the cells are protein complexes known as tight junctions, which regulate which substances can pass between the cells.

When this regulation changes, intestinal permeability can increase.

Experimental research shows that psychological stress can affect the intestinal barrier, partly through signalling involving CRH and mast cells. Human studies have also shown stress-related changes in intestinal permeability, although results vary between different studies and types of stress.

“Leaky gut” therefore does not mean that holes develop in the intestine. It refers to altered regulation of the permeability of the intestinal barrier.

SIBO – When Bacteria Are in the Wrong Place

The large intestine normally contains very large numbers of bacteria. The small intestine, on the other hand, has a considerably lower bacterial density.

With SIBO – Small Intestinal Bacterial Overgrowth – there is an increased amount and/or altered composition of microorganisms in the small intestine.

This is an important distinction.

SIBO is therefore not only about which bacteria we have, but also where in the gastrointestinal tract they are located and what they are doing there.

When bacteria have greater opportunity to metabolise nutrients already in the small intestine, this can, among other things, lead to increased fermentation and the production of various microbial metabolites.

SIBO has also been associated with altered motility, immune activation and effects on the intestinal lining.

Can SIBO Contribute to Leaky Gut?

There are biological reasons to connect bacterial overgrowth with intestinal barrier function, but the relationship is complex.

Studies have shown increased small intestinal permeability in certain forms of bacterial overgrowth, while other studies – for example, among people with IBS – have not shown that SIBO itself explains the increased permeability.

It is therefore more accurate to view SIBO, inflammation, altered barrier function and impaired motility as potentially interacting processes rather than saying that SIBO always causes leaky gut.

When Substances from the Gut Reach the Bloodstream

This is where research into the gut-brain axis has taken an important step forward.

Bacteria in the gut produce a large number of small molecules – microbial metabolites – when they break down substances from our diet.

These metabolites do not necessarily remain in the gut.

Some can be absorbed through the intestinal lining, enter the bloodstream and potentially affect organs in other parts of the body.

Two interesting examples are imidazole propionate (ImP) and trimethylamine N-oxide (TMAO).

ImP – A Bacterial Metabolite Linked to the Brain’s Stress System

Imidazole propionate, or ImP, is produced when certain gut bacteria metabolise the amino acid histidine.

ImP has previously received attention primarily in research on type 2 diabetes, insulin resistance and metabolic health.

But new research has opened up an entirely new area.

A study published in 2025 showed that bacteria-produced ImP could reach the bloodstream and the brain.

In experimental models, elevated ImP affected, among other things, gene expression in the hypothalamus and the balance between GABAergic and glutamatergic signalling – two central systems involved in neuronal activity in the brain.

The researchers also found links to stress-related behaviour.

In humans, higher ImP levels were associated with a poorer ability to cope with stress and increased emotional eating.

This does not mean that ImP causes mental health problems. But the findings demonstrate something fundamentally important:

A metabolite produced by gut bacteria can reach the brain and influence neuronal function.

TMAO – Another Link Between Bacteria and the Rest of the Body

TMAO, trimethylamine N-oxide, is another metabolite linked to bacterial metabolism in the gut.

The process begins when bacteria metabolise substances such as choline and carnitine into trimethylamine (TMA). TMA is absorbed and primarily converted in the liver into TMAO.

TMAO has mainly been studied in relation to cardiovascular disease, kidney function and metabolism. In recent years, research has also investigated possible connections with brain function.

For example, studies have found associations between higher TMAO levels and cognitive impairment, and TMAO is now being studied as a possible part of the metabolic communication within the gut-brain axis.

At the same time, it is important to distinguish between association and causation. TMAO is influenced by factors including diet, microbial metabolism, liver function and kidney function, and it is not yet clear to what extent TMAO itself contributes to different neurological or psychological conditions.

From Gut Microbiota to Gut Function

This partly changes how we can think about the gut-brain axis.

The question is not only:

“Which bacteria are present in the gut?”

At least equally interesting questions are:

Where are the bacteria located?

Which substances do they produce?

How does the small intestinal barrier function?

And which of these signals reach the bloodstream, nervous system and ultimately the brain?

Two people could therefore theoretically have a similar bacterial composition in a stool sample while still having different microbial activity and different conditions in the small intestine.

A Possible Vicious Cycle: Stress → Gut → Brain

The bidirectional communication also gives rise to an interesting model:

This should not be interpreted as meaning that stress automatically causes SIBO or that SIBO causes mental health problems.

Rather, the model illustrates why the gut-brain axis is a cycle rather than a one-way signalling pathway.

The brain can change the conditions in the gut – and changes in the gut can in turn create new signals back to the brain.

What Does This Mean for Mental Health?

In recent years, research on the gut-brain axis has moved from relatively general associations between the “gut microbiota” and mental wellbeing towards more detailed biological mechanisms.

Researchers are now investigating, among other things:

• microbial metabolites
• intestinal permeability
• immune activation
• vagal signalling
• the HPA axis
• neurotransmitter systems
• the interaction between the intestinal barrier and the blood-brain barrier

Changes within these systems have been linked to stress, anxiety, depression, emotional eating and cognitive function, among other things.

But the research field is still young.

The fact that a metabolite or change in the gut is associated with a mental health condition does not mean that it causes the condition. Mental health is influenced by a large number of biological, psychological and social factors.

The gut is one part of this complex system – not the whole explanation.

The Gut and Brain – An Ongoing Conversation

Perhaps the most important insight from current research is therefore that the gut and brain should not be viewed as two separate organs.

They are in constant communication.

Through the stress system and the autonomic nervous system, the brain can influence gut motility, the immune system and barrier function.

At the same time, the gut can send information back through the vagus nerve, immune system and bloodstream.

And new research shows that even small molecules produced through bacterial metabolism can be part of this communication.

This is why the next generation of research into the gut-brain axis will likely focus less on simply which bacteria are present in the gut – and more on where they are located, what they produce and how these substances interact with human physiology.

References

1. Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014;63(8):1293–1299. doi:10.1136/gutjnl-2013-305690.
2. Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 2011;62(6):591–599.
3. The microbial metabolite imidazole propionate modulates hypothalamic activity and stress-induced behaviors. 2025. PMID: 41297540.
4. Liu M, et al. The role of gut microbiota-derived trimethylamine N-oxide in the pathogenesis and treatment of mild cognitive impairment. Int J Mol Sci. 2025;26(3):1373. doi:10.3390/ijms26031373.
5. Small intestinal bacterial overgrowth: microbiome dysregulation, gut-brain axis disruption, and systemic consequences. 2026. PMID: 42378001.