Microbiota related to the gut-brain axis

The influence of the gut-brain axis on the brain is a relatively new research angle, which has partly been made possible by recent technological developments (DNA analyses in particular) that allow the composition of microbiota to be studied in detail. For instance, it has been shown that signals from the brain can influence the composition of the microbiota. In stressfull situations certain signals triggered in the brain,such as transient stress or fear, can affect our bowel function and cause constipation or diarrhoea. Prolonged stress can even lead to changes in the composition of the microbiota. The reverse is also possible: an altered microbiotal composition can result in altered signals to the brain and thereby affect cognitive functions. This means the microbiota are directly involved in the communication via the gut-brain axis.

With research now progressing to the stage of trials with human subjects, the interaction between intestinal microbiota and the brain is attracting attention not only from the research field but increasingly also from clinicians in the fields of neurology, psychology and psychiatry. This attention is currently focused largely whether influencing the microbiota can effect changes in mood and in how stress is experienced.

A great deal of preclinical research with mice has been done concerning the mechanisms enabling the bidirectional communication via the gut-brain axis. This research has demonstrated that, apart from the microbiota, there are specific probiotic bacteria that influence brain function1. As mentioned before, communication between the gut and the brain is transmitted via neural, hormonal, metabolic and immunological pathways. The following sets out a number of these pathways.

Influence of microbiota on the central nervous system

The intestines are surrounded by a fully autonomous nervous system known as the enteric nervous system (ENS), also referred to as the “second brain”. The ENS has a direct link to the central nervous system via the vagus nerve, which transmits signals from the brain to the gut and vice versa2. The ENS controls gut peristalsis, fluid exchange via the mucosal surfaces and the secretion of gut hormones.

Gut bacteria are important for maintaining healthy mucosal surfaces. In that respect, they play a key role in the interaction with the ENS and thereby also in the generation of signals to the brain via the gut-brain axis.

Bravo et al. have lifted a corner of the veil covering the mechanisms of the interaction between the gut and the brain3. They demonstrated that treatment with the probiotic strain Lactobacillus rhamnosus led to a differentiated expression of gamma-aminobutyric acid (or GABA) in specific regions of the brain. They also saw a reduction in stress-induced corticosterone levels, that was linked to a noticeable decrease in anxiety- and depression-related behaviour.

What was noteworthy about this trial was that this improvement was only seen in individuals with an intact vagus nerve,  suggesting that this nerve plays a crucial role in how probiotics affect behaviour.

The role of microbiota in brain function has been confirmed in various mouse trials4 5, which showed, for instance, that mice without microbiota behave anxiously and that this can be reduced by administering a probiotic (in this case Bifidobacterium infantis) or amplified by administering the enteropathogen Escherichia coli6.

There have now also been trials demonstrating the communication between gut and brain via hormonal7 and immunological8 pathways. A preclinical trial conducted by D’Mello et al. specifically showed that probiotic strains can also influence the immunological pathway. By administering a mix of probiotic strains, this trial resulted in an improvement of inflammation-induced behavioural patterns. The communication related to this was transmitted via the peripheral immune system9.

Role of intestinal barrier

In addition to the specific pathways described above, the intestinal barrier function plays a prominent role in the gut-brain axis10. It has been known for some time that the microbiota and the intestinal barrier jointly play a key role in homeostasis and in the body’s defence against pathogens. Prolonged stress, drug use or infections can alter the composition of the intestinal microbiota, disrupting the integrity of the intestinal barrier. The intestinal barrier, which has a contact surface approximately equal to that of a tennis court, has the thickness of a single cell and is protected by a mucus layer, with the cells interconnected by so-called tight junctions. If this line of defence is breached, greater numbers of immunomodulating substances, such as lypopolysacchararides (LPS), can enter the body. This increased gut permeability most often leads to low-grade inflammation and is associated with a range of conditions, including a greater amounts of inflammatory bowel diseases and diabetes mellitus11 12. These diseases often coincide with depression,  suggesting that depression could be directly linked to a “leaky gut”1. Depression and other stress-related conditions, including anxiety and panic attacks, are directly associated with low-grade bowel inflammation10.

Probiotics offer new perspective

Remarkably, many psychological and psychiatric conditions, including schizophrenia, ADD and Parkinson’s disease, are often accompanied by gastrointestinal symptoms. Some of these can be explained by the side effects of drugs. A high comorbidity with conditions involving low-grade inflammation is also seen. The incidence of psychological distress (including depression) is 10-30% higher in people with diabetes and, conversely, depression is associated with an increased incidence of diabetic complications13.
Because of the sometimes severe side effects, the only drugs available for many psychiatric conditions are not prescribed in mild cases, let alone in cases with increased risk or contraindications.
This means there is an urgent need for a new option, especially for the latter category of patients. Given the enormous impact of the microbiota on brain and behaviour, looking into the therapeutic options in this area seems an obvious step14. Probiotics can influence the composition and activity of intestinal microbiota and thereby the gut-brain axis as well. For that reason, probiotics offer a new perspective when it comes to (supplementary) treatment in conditions involving the gut-brain axis.

Probiotics are a safe treatment with a negligible side effect profile. The specific properties of the strains making up the probiotic are key.

The use of probiotics can be stopped without restrictions and at any time. 

References

  • 1. a. b. Slyepchenko, A. et al. Intestinal dysbiosis, gut hyperpermeability and bacterial translocation: missing links between depression, obesity and type 2 diabetes? Current pharmaceutical design (2016).
  • 2. Mayer, E. A. Gut feelings: the emerging biology of gut-brain communication. Nature reviews. Neuroscience 12, 453-466, doi:10.1038/nrn3071 (2011).
  • 3. Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America 108, 16050-16055, doi:10.1073/pnas.1102999108 (2011).
  • 4. Cryan, J. F. & Dinan, T. G. More than a gut feeling: the microbiota regulates neurodevelopment and behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 40, 241-242, doi:10.1038/npp.2014.224 (2015).
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  • 6. Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. The Journal of physiology 558, 263-275, doi:10.1113/jphysiol.2004.063388 (2004).
  • 7. Neuman, H., Debelius, J. W., Knight, R. & Koren, O. Microbial endocrinology: the interplay between the microbiota and the endocrine system. FEMS Microbiol Rev 39, 509-521, doi:10.1093/femsre/fuu010 (2015).
  • 8. Logan, A. C., Jacka, F. N. & Prescott, S. L. Immune-Microbiota Interactions: Dysbiosis as a Global Health Issue. Current allergy and asthma reports 16, 13, doi:10.1007/s11882-015-0590-5 (2016).
  • 9. D’Mello, C. et al. Probiotics Improve Inflammation-Associated Sickness Behavior by Altering Communication between the Peripheral Immune System and the Brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 35, 10821-10830, doi:10.1523/jneurosci.0575-15.2015 (2015).
  • 10. a. b. Kelly, J. R. et al. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Frontiers in cellular neuroscience 9, 392, doi:10.3389/fncel.2015.00392 (2015).
  • 11. Moss, A. C. The meaning of low-grade inflammation in clinically quiescent inflammatory bowel disease. Curr Opin Gastroenterol 30, 365-369, doi:10.1097/mog.0000000000000082 (2014).
  • 12. Pitsavos, C. et al. Association Between Low-Grade Systemic Inflammation and Type 2 Diabetes Mellitus Among Men and Women from the ATTICA Study. The review of diabetic studies : RDS 4, 98-104, doi:10.1900/rds.2007.4.98 (2007).
  • 13. de Groot, M., Anderson, R., Freedland, K. E., Clouse, R. E. & Lustman, P. J. Association of depression and diabetes complications: a meta-analysis. Psychosomatic medicine 63, 619-630 (2001).
  • 14. Borre, Y. E., Moloney, R. D., Clarke, G., Dinan, T. G. & Cryan, J. F. The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. Advances in experimental medicine and biology 817, 373-403, doi:10.1007/978-1-4939-0897-4_17 (2014).