Have you ever experienced a "gut feeling", “a knot or butterflies in your stomach” when feeling nervous? These sensations hint at the connection between your brain and your gut. Let’s delve deeper into this intriguing connection!

3 Controllers

When it comes to digestion, there are 3 main controllers- the central nervous system

(mostly the brain), the autonomic nervous system (a network of nerves that regulates involuntary physiologic processes including heart rate, blood pressure, respiration, digestion, and sexual arousal), and the enteric nervous system (a network of nerves that regulates digestive processes and movement of food through the digestive tract).

The interplay between central and autonomic nervous system

There is two-way communication between our brain and digestive system. At a structural level, this communication occurs through nerves that run between the brain and the digestive system. The autonomic nervous system is largely in charge of these interactions. Sensory, chemical, mechanical, and pain signals are conveyed back and forth, using autonomic nerves as their pathways. This allows the brain to understand the state of the gut and the gut to take orders from the brain. The autonomic nervous system consists of two main branches: the sympathetic and parasympathetic systems.

The parasympathetic nervous system is largely responsible for turning on the "rest and

digest" functions. In contrast, the sympathetic nerves are often called the “fight or flight” system. They take care of the “activation”- helping us stay alert, and respond to stress by gearing up our organs. Imagine facing a wild bear in the forest - you need to be alert, and focused, with your heart, lungs, and muscles ready to flee; there's no time for digesting your dinner, or love-making, so these functions are suppressed during stress response. The balance between the two systems is crucial for optimal function and the state of wellbeing.
The picture below shows the two main branches of the autonomic nervous system and their main functions:

Enteric nervous system

The gut has a vast network of nerves called the enteric nervous system, nicknamed “gut brain”, or “second brain” by some. This is because it can function without input from the brain. It contains roughly the same amount of neurons as the spinal cord. Its main function is the secretion of digestive juices and motility (movement). It has its own circulatory, lymphatic, and immune systems. It uses the same chemical messengers (neurotransmitters) as the brain, the most important one being serotonin. When you think about it, the importance of the gut is enormous for our survival, so it makes sense that it evolved with its own “traffic controller”, and an “army of workers”. The main communication highway for the enteric nervous system is the vagus nerve - perhaps the most important parasympathetic nerve. About 80-90% of communication through the vagus nerve is in the gut → brain direction, thus the gut letting the brain know what’s going on.

Chemical messengers

In addition to the direct connection via nerves, the gastrointestinal tract and the brain also communicate via a complex communication network involving chemical messengers conveying information among the gut, brain, endocrine system (hormones), metabolism (energy extraction/production process), and the immune system. Another important communication pathway between the gut and the brain is via the metabolome- chemical compounds produced by the gastrointestinal cells and microbes residing within our gastrointestinal tract. Metabolome is sometimes referred to as the “gut-brain axis”.

Stress & Digestion

When our body or mind is feeling under pressure, the sympathetic nervous system is turned on to help us handle it- the body needs to be ready to “fight”. Some of the notable adaptations to stress are: blood flow is turned towards survival organs, such as muscles and heart, and away from those that are not necessary for immediate survival, such as the digestive tract. In the digestive tract this results in: ·

reduced saliva production
decreased stomach acid, and
other digestive juices production
decreased/ unsynchronised movement of the gut
delayed emptying of stool

These adaptations are necessary for survival in the short term-while facing an “acute” event. However, if these adaptations continue for a long time due to a perceived state of stress, it is easy to see how they can be detrimental to our digestion and general health. Many of us live in a state of chronic or frequent stress, which creates a state of sympathetic dominance, characterized by the adaptations described above. Some of the notable triggers for the state of chronic stress are:

trauma - emotional or physical; present or past
trauma can affect our limbic system- the brain’s “alarm system”, which remains constantly switched on, creating a state of constant perceived stress, even if the event happened in the past. - body remembers! (I’ll dedicate a blog to this topic soon)
physical challenges our body faces, such as - physical illness, vigorous exercise, shift work, etc.
mental and emotional challenges - stressful home or professional life, having a lot of tasks to juggle all the time (high mental load), the many different added life challenges
environmental challenges - we are almost constantly exposed to countless pollutants- chemical, mental, and physical

The link between the Digestive Tract and the Brain is Bi-directional

Thus, we have established that chronic stress can result in a dysfunctional digestive system. This can have a number of detrimental effects: poorly digested food and slow or uncoordinated movement of bowels can lead to food staying in the gut for too long and putrefying/ fermenting, thus producing noxious gases, which irritate the gut further, causing low-grade or overt inflammation. It can also create a change in the environment within the gut, which can lead to the overgrowth of certain microbial species, hence tipping the microbes away from optimal balance. Some of the overgrown species are known to produce toxic compounds, which further irritate the gut and can “leak” into the body, causing seemingly unrelated issues elsewhere. Furthermore, there is evidence that chronic stress precipitates functional, and structural changes in the enteric nervous system, making it “hypersensitive”. This is relevant for the understanding of irritable bowel syndrome and similar conditions. [i]

There is a lot of research, linking stress and so-called functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), functional dyspepsia (reflux), as well as other digestive disorders, including inflammatory bowel disease. The prevalence of depression, anxiety, autism spectrum disorder, and a history of emotional, sexual, or physical abuse or

adverse childhood events “ACEs”, is much higher in people with functional gastrointestinal disorders, than in the general population. In addition, all these disorders have been linked with specific microbiome disturbances.[ii]

On the other hand, imbalances in the gastrointestinal system can directly affect our mental state and behavior, causing symptoms such as anxiety, insomnia, low mood, irritability, anger, autistic behavior, etc. This is partially explained by the sympathetic dominance, described above.However, over the recent decades, ample evidence has been mounting, attesting to the crucial role of the microbiome and the metabolome for mental and cognitive health. Numerous studies have implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. [iii] This makes good sense when you consider that many microbes residing in our gut produce a range of neuroactive substances (more on this below).

Metabolome

(Or how can microbes in our gut affect our mental state, health, well-being, and even cognition?)

As mentioned above, in addition to communication via nerves and hormones, the communication between the gut and the brain also happens via the gut metabolome. Research demonstrates that there is a huge variety of compounds produced by, or within the digestive system. Many of these affect our health and well-being. The most important are:

Neurotransmitters (chemical messengers that carry signals between nerve cells). These are produced by our own cells, but also by a range of microbes that reside within our gut. (PMID29903615) The most notable ones are:
- SEROTONIN: helps regulate sleep, appetite, and mood. It also plays an important role in the modulation of pain. On the gut level, it regulates gastrointestinal secretions and peristalsis (movement of bowels). 80-95% of serotonin in our body is produced in the gut- mostly to moderate its own function, however, there are studies that show that it can cross the blood-brain-barrier and thus affect the brain.
GABA (gamma-aminobutyric acid): affects gut motility, gastric emptying, and acid secretion. On the brain level, it has a calming effect and modulates the perception of pain.
Other neurotransmitters, such as noradrenaline/ norepinephrine and dopamine are also produced by gut bacteria and exhibit local as well as systemic effects.
Tryptophan is an amino acid, essential for the production of serotonin. An unbalanced microbiome and stress hormones can shunt it through pathways that produce toxic metabolites, including indoles and other metabolites with known neurotoxic effects.
Histamine is another neuroactive compound produced by the gut cells, as well as some resident gut bacteria. Gut also plays an important role in breaking down histamine ingested in food. Histamine excess causes an array of neuropsychiatric symptoms, including anxiety, restlessness, insomnia, etc. (A dedicated blog is coming in the near future.)
Short-chain fatty acids, such as butyrate and propionate, are products of gut microbiome with many health benefits, including anti-inflammatory, immunoregulatory, anti-obesity, neuroprotective, cardioprotective, etc.
Proinflammatory molecules, such as LPS (lipo-poly sacharide), ammonia, etc. Certain microbial species produce these and other molecules, known to trigger inflammation in, and outside of the gut [iv]
Vitamins, including vitamin B12: vitamin B12 is exclusively synthesized by bacteria. A healthy gut and balanced microbiome are needed for it to be absorbed and utilized by the body. Deficiency of this crucial nutrient can manifest as anemia, fatigue and a range of neurological symptoms.
A wide variety of other compounds, including hormones, neuropeptides, bile acids, choline metabolites, lactate, etc.

Gut Defense System

The walls of our digestive tract serve as part of our defense system. This important barrier protects us from allergens, toxins and other potentially harmful substances we ingest. A sick gut, and/ or out-of-balance microbiome can result in inflammation, which makes this barrier swollen and porous, thus making it less efficient. This is termed increased intestinal permeability. Through this “leaky” barrier, toxins, allergens and other harmful substances can now escape into the body and affect any of our organ systems, including our brain, causing a wide range of symptoms, including fatigue, insomnia, brain fog, anxiety, impaired focus, etc.

A sick gut means an impaired ability to absorb nutrients

Inflammation resulting from some of the above-mentioned processes can result in poor absorption of nutrients from food, which can further influence our brain health and general well-being.

In summary

There is a bi-directional relationship between the brain and the gastrointestinal system, influenced by many factors. Chronic stress and trauma can result in digestive and mental health disorders by switching on the constant stress response. The vagus nerve plays a crucial role in good digestive and mental health and provides an important window

for intervention. The gut microbiome can influence our mental state and behaviour by producing a range of compounds (metabolome)- some harmful, some with beneficial effects. A sick gut makes our nervous system more vulnerable.

In the next blog, I will explore ways to prevent, treat, or mitigate the processes describedhere.

[i] https://pubmed.ncbi.nlm.nih.gov/21090962/

[ii] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469458/

[iii] https://www.nature.com/articles/s41593-023-01361-0, https://www.cas.org/resources/cas-insights/emerging-science/how-your-gut-microbiome-linked-depression-and-anxiety, https://journals.physiology.org/doi/full/10.1152/physrev.00018.2018, https://pubmed.ncbi.nlm.nih.gov/31460832/, etc.

[iv] https://www.nature.com/articles/s41569-022-00737-2