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Gut microbes – the key to gut-brain communication

Whenever you experience a “gut feeling” or felt “butterflies in your stomach”, you are likely getting signals from your ‘second’ brain, the gut. The communication system between your gut and brain is called the gut-brain axis (Carabotti et al., 2015; Cryan and Dinan, 2015; Mayer et al., 2015). In practice, it involves three actors:

  • the intestine (the gut)

  • gut microbiota (gut flora)

  • the brain.

This communication is bidirectional, meaning that it functions in two directions. The brain effects our gut function via the sympathetic (‘fight or flight’) and the parasympathetic (‘rest and digest’) nervous systems. The balance of signals from these two inputs affects digestion, secretion of digestive enzymes, absorption of nutrients, the speed at which food moves through the digestive system, and level of inflammation in the gut. On the other side, the gut and its microbiota communicate subtle changes within the gastrointestinal tract to the brain impacting its function and our behaviour. Disturbance in the gut-brain axis is believed to be involved in the development of several gastrointestinal disorders e.g., irritable bowel syndrome, as well as brain and mental diseases including anxiety, depression, autism, or Parkinson’s (Rhee at al., 2009; Mayer, 2011; Cryan and Dinan, 2012, Mayer et al., 2014; Appleton, 2014; Santos et al., 2019). Therefore, balancing the brain-gut axis has become an important therapeutic target for gastrointestinal and psychiatric diseases, such as inflammatory bowel disease, depression, and posttraumatic stress disorder (Evrensel and Ceylan, 2015; Leclercq et al., 2016¸Bonaz et al., 2017).


WHAT EXACTLY IS THE CONNECTION BETWEEN THE BRAIN AND THE GUT?


Bidirectional communication between the gastrointestinal tract and the brain is regulated at neural, hormonal, and immunological level, and involves:


1. Central nervous system - brain and spinal cord.


2. Autonomic nervous system - sympathetic and parasympathetic; including enteric nervous system (ENS) and vagus nerve:

  • The parasympathetic nervous system is responsible for a ‘rest and digest’ response, promoting calming of the nerves return to regular function, and enhancing digestion.

  • The sympathetic nervous system promotes a ‘fight or flight’ response, energy generation, and digestion suppression.

  • The ENS is the largest component of the autonomic nervous with a dense network of nerve cells stretched across the entire surface of our intestines (Schemann and Neunlist, 2004; Schemann, 2005; Furness et al., 2014). It is estimated that the human ENS contains about 100–500 million nerve cells (neurons). In relation to the structure, function, and chemicals the ENS is similar to the brain, therefore, it has been described as ‘the second brain’ (Gershon, 1999). The ENS receives inputs from the autonomic nervous systems but can also function independently. It coordinates the digestive enzymes secretion by the stomach and regulates the process of muscle contractions of the gastrointestinal tract that moves food along. Moreover, the ENS system remains in constant contact with the brain, and this relationship is extremely important for the whole body.

  • The vagus nerve is the longest nerve in our body (Furness et al., 2014; Bonaz et al., 2018) and a major nerve of the parasympathetic nervous system. It is an important pathway for bidirectional communication between gut microbes and the brain. The most important function of the vagus nerve is to bring information of the inner organs, such as gut, liver, heart, and lungs to the brain. As much as 90% of the nerve impulses that follow the path of the vagus nerve are sent from the gut to the brain.

3. The hypothalamic–pituitary–adrenal (HPA) axis - the neural system that mediates the secretion of cortisol, which influences the body’s responses to stressors of any kind (Tsigos and Chrousos, 2002).


4. Gut microbiota - a collection of microbes in the gut.


INTESTINAL MICROBIOTA - AN ESSENTIAL PART OF THE GUT-BRAIN COMMUNICATION


The number of microorganisms inhabiting the large intestine exceeds ∼10 times the number of human cells and over 100 times more genes (microbiome) than the human genome. Microbiota (collection of microbes) in the gut weigh 1-2kg (Backhed, 2005; Gill et al., 2006; Walker et al., 2014). The gut microbiome serves numerous crucial functions in the human body. Some of the roles it serves include:

  • ability to break down plant-based complex sugars that are not processed by humans

  • development of the immune system

  • defense against infections

  • absorption of nutrients

  • production of numerous vitamins and enzymes from food, such as vitamin B12, folic acid and vitamin K.


HOW THE GUT MICROBES INTERACT WITH THE GUT-BRAIN AXIS?


The microbes of the gut microbiota interact with the gut-brain axis in the following ways:


1. The vagus verve. Certain microbial stimuli activate the vagus nerve and signals transmitted to the brain that leads to changes in the neurochemistry of the brain and therefore our behaviour (Forsythe et al., 2014). For example Lactobacillus rhamnosus effects neurotransmitter receptors in the central nervous system, directly activates vagal neurons and reduces anxiety and depression-like symptoms (Bravo et al., 2011).


2. Gut hormones. Gut can communicate with the brain via hormonal signalling. Intestinal bacteria release factors that are known to affect production of several neuropeptides such as peptide YY, neuropeptide Y (NPY), cholecystokinin, glucagon-like peptide-1 and -2, and substance P (reviewed in Holzer and Farzi, 2014). Neuropeptides are molecules that function as mediators in the nervous system and between neurons and other cells. These neuropeptides then enter the bloodstream and/or directly influence the ENS.


3. Interference with tryptophan metabolism. Gut microbiota plays an important role in tryptophan metabolism. Tryptophan is an essential amino acid and used by cells to produce proteins, including brain chemical called serotonin. Approximately 95% of serotonin is produced by gut mucosal cells and implicated in regulation of secretion, smooth muscle contraction and relaxation, and pain perception, whereas in the brain serotonin regulates mood and sleep (Gershon, 2013).


4. Regulation of the immune system. The gut microbiota is a very important stimulator of the immune system and affects immune cells located in the gut mucosa. These immune cells release cytokines that are important in host responses to inflammation and infection. The intestines, in addition to their own nervous system and bacterial flora, also have an immune system known as gut associated lymphoid tissue (GALT). GALT is the largest immune network in the body which comprises 70% of the total body’s immune system.

5. Production of microbial metabolites. Short-chain fatty acids (SCFAs), including acetate, butyrate, lactate, and propionate, are the main metabolites produced by bacterial fermentation of dietary fibre and resistant starch in the gastrointestinal tract (Pascale et al., 2018). SCFAs have been shown to possess neuroactive properties influencing the brain function (Tan et al., 2014; Stilling et al., 2016; Fung et al., 2017; Dalile et al., 2019). They are able to stimulate sympathetic nervous system and serotonin release, thus influence our memory and learning process. Many species of Lactobacillus and Bifidobacterium produce gamma-aminobutyric acid (GABA), which is the main neurotransmitter in the brain. In addition, Candida, Escherichia, and Enterococcus have been shown to produce serotonin, while some Bacillus species produce dopamine.

CONCLUSIONS


The idea that the gut microbes influence the brain biochemistry, and therefore also behaviour, is widely understood and accepted. As much as 90% of the nerve impulses that follow the path of the vagus nerve are sent from the gut to the brain. Therefore, gut plays an important role in regulating our mental health. The ENS is also connected with the immune system and its cells. These cells survey the digestive system and transfer information back to the brain, such as whether there is infection in the gut or insufficient blood flow. Scientists have only recently begun to investigate the mechanisms behind the gut-brain complex interaction and communication. This communication link is now at the core of several area of research – psychiatry, gastroenterology, neurology. New treatment options e.g., vagus nerve stimulation (VNS) and meditation, are available for modulation of the brain-gut axis. Also, one cannot forget about traditional herbal medicine. Nature has a lot of plants and compound that modulate the gut-brain axis. These methods are beneficial in mood and anxiety disorders, and conditions associated with increased inflammation (Rod, 2015; Koopman et al., 2016¸ George et al., 2018).

 

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