The Gut-Brain Connection: Can Nutrition Really Impact Mental Health?

The gut microbiome has been a hot topic in the last 10 years and many studies on the subject are being published every single day. Researchers explore the relation between the gut microbiome and chronic diseases, the immune system, the digestive system, among other topics. The gut microbiome is made of more than 10^14 microorganisms, including bacteria, fungi, viruses, and protozoa. Scientist are still working on identifying these different organisms and to understand their role in human health.

If you want to have an overview of what is the gut microbiome and what we know it about, check out this article: Gut Microbiome 101.


One of the subjects that generates many questions in the area of the gut microbiome is the link between our gut and mental health. And fortunately there is a lot of answer!


Let's take a deep dive and discover what we know so far!


Why do we call our gut our ''second brain''?

If you ask most people what is the function of our gut, their answer would likely be things related to digestion. Well, the truth is, our gut plays so many more functions than just digestion! The gut-brain-axis is define as the bidirectional relation between our gut and our brain (aka. a 2 way street!). Decades ago, the belief was that the brain was the executive commander of our entire body. Now, we realize that the gut is not a follower but rather a commander as well!


The gut-brain-axis impacts the central nervous system, the autonomic nervous system, the enteric nervous system and the pituitary gland. Here's a quick anatomy and physiology review:

Autonomic System: includes sympathetic and parasympathetic system, regulates body functions such as the heart rate, respiration and digestion. These functions are mainly unconscious behaviours (THANK GOD- can you image we had to consciously digest our food and not forget to breathe at the same time!).

Enteric Nervous System: is a subdivision of the autonomic system and includes the neurons that govern the function of the gastrointestinal tract.

Pituitary Gland: is located in the brain (only the size of a pea!) and plays a key role for mediating the stress response, via the hypothalamic-pituitary-adrenal axis (HPA). The HPA is part of the limbic system, an area of the brain mainly involved in memory and emotional responses that are activated in presence of stress and elevated pro-inflammatory cytokines (1). The activation of this system leads to the release of cortisol, a major stress hormone that affects many human organs.


All of these systems are communication lines for the brain to influence the activities of intestinal functional effector cells, such as enteric neurones, immune cells, epithelial cells and a few more. These same cells are under the influence of the gut microbiome.

Moreover, epithelial cells in the lining of the small intestine have a variety of functions that are important to understand when looking at the role of the gut microbiome. Enterocytes are the most abundant epithelial cells, they absorb water, ions, nutrients et secrete immunoglobulins (6).

Goblet cells are responsible for secretion of mucus, which protects the lining of the intestine. Actually, intestinal bacteria especially live in the mucus where they can interact with food and the membrane. Therefore, an adequate mucus production by the goblet cells is crucial for both protection of the intestinal walls, but also for the activity of intestinal bacteria.

Paneth cells are responsible for the secretion of antimicrobial agents (6) (aka Immune System!).

Then, there's the enteroendocrine cells. These cells actually form the largest endocrine organ in the body and play a crucial role in the control of GI secretion, motility, postprandial glucose levels, metabolism and regulation of food intake (2). Enteroendocrine cells secrete GLP-1 and PYY, which are anorexigenic hormones (appetite suppressant hormones) implicated in the food intake regulation. These cells also secrete serotonin, a neurotransmitter with multiple functions, including regulation of emotion, stress response, appetite, gastric secretion, gastric motility and more (5). General population knows serotonin as a key player in mood regulation, we know it as the '' happiness '' hormone, but as you can see, it plays several more important roles. Actually, up to 95% of serotonin is produced in our gut (2, 4, 5)! Furthermore, recent studies have highlighted the role of enteroendocrine cells sensory transmission by showing direct connections between these cells and the nervous system (4).

95% of serotonin (happy hormone) is produced in our gut

The principal mechanisms happening from the gut microbiome to the brain include the production of neurotransmitters, such as serotonin, the protection of the intestinal barrier, the production of bacterial metabolites, immune regulation and the modulation of enteric signals.

The mechanisms from the brain to the gut microbiome include alteration in motility, intestinal permeability, mucus production and immune function (1)!


Not only digestion happening here, right?


How does the gut-brain-axis impact our food intake?

As previously mentioned, cells in our gut play a role in the regulation of our food intake by producing neurotransmitters and hormones that communicate to the brain. Numerous data show that what we eat and when we eat is likely affected by the function and composition of our gut microbiome (4). In many conditions where food intake behaviours are dysregulated, such as obesity and anorexia nervosa, there are also some dysregulation and alteration in gut microbiota (4). In order to increase their fitness and survive in the gut, microbes may use several mechanisms to influence food behaviour by inducing cravings, dysphoria (state of dissatisfaction), modifying dopamine production and altering our taste receptors (8). These observations are hard to prove experimentally, but an interesting study made with Drosophila (commonly called '' fruit fly ''. They are actually quite useful in research and pointed out a key role for the gut microbiome composition in food choice behaviour. Conclusions from that study are that intestinal bacteria could play a role in detecting the absence or lack of certain nutrients and therefore could contribute in generating a '' craving '' for the missing nutrients (7).

However, more studies are needed to assess the possible role of gut microbiota composition and regulation of '' craving ''.


Interestingly, another evidence of the possible link between our microbe and craving is the difference in gut microbiome of people depending on their preferences for chocolate. People eating identical diets, but only differing from if they are '' chocolate desiring '' or '' chocolate indifferent '', have different microbial metabolites in their urine (8). When comparing food intake of regular mice with germ-free mice( i.e. mice without any gut microbiome living in sterile environment), germ-free mice have a higher fat intake than regular mice (4). Again, these observations put more emphasis on the influence of intestinal bacteria on food behaviour.


Another possible mechanism by which the gut microbiome can impact food intake behaviour is by influencing the ability to sense and taste nutrients. For example, anorexia nervosa is associated with an altered taste perception and weight gain has been shown to improve these impairments. More information regarding eating disorders and gut microbiome can be found right here. In obesity, there's also an association with a decreased responsiveness to fatty and sweet tastes, which results in requiring a higher quantity of these type of food to attain the same level of taste perception (4).


What we eat and when we eat is likely affected by the function and composition of our gut microbiome.

In summary, microbes in our gut can modulate our eating behaviour in order to increase their fitness and survive in the gut. They may generate cravings for nutrients that are missing or that they can metabolize by releasing toxins and they can induce dysphoria until we eat foods that enhance their fitness. Also, microbes may be able to influence the reward system by increasing dopamine production and modulating satiety signals (8).

Now, you might wonder, what's the link with mental health? This introduction to the topic is important to the growing body of evidence that the food we eat impacts our gut composition, and that our gut composition can have an impact on several diseases, including mental health. An example that most people can relate to is the impact of stress. When we're experiencing a stressful situation, we often feel it in our stomach. We're either not hungry at all, or feeling like snacking on everything... Numerous studies have shown, both in animal and clinical models, that chronic stress has a negative impact on food behaviour and is correlated with a diet higher in calories, reduced intake in fruits and vegetables, increased intake of sweet and fatty foods and an overall lower healthy eating index score (4). Let's take a deeper look to mental health and gut microbiome now.


How does our gut health impact our mental health? Can gut issues lead to mental health issues?

Interestingly, the first time a link between mental health and gut microbiome was studied in 1822 by Dr William Beaumont who is known as the '' Father of Gastric Physiology ''. His studies led to important finding, digestion is impacted by our mood (3). This opened the door to a potential link between our emotions and digestion.


Nowadays, the link between mental health and the gut microbiome has been shown mainly in animal models. For instance, the brain of germ-free mices (again, mice without gut microbiomes) is different than the one from normal mice and the ingestion of specific strains of bacteria has an effect on behaviour (4). Unfortunately, human studies of good quality are still only found in small number and are often really hard to achieve due to interfering factors, such as medications, the variability of mental health conditions and the sex of participants. However, there are some promising results in both animal and clinical models that allow a better understanding of the link between gut microbiome and mental health.


To start off, mental health symptoms in disorder such has major depression and anxiety disorder include change in appetite, loss of energy, fatigue, gastrointestinal symptoms (nausea, bloating, etc.) and anhedonia(i.e inability to feel pleasure) can all have an impact of eating behaviour resulting in less energy, less enthusiasm to eat, less appreciation and less motivation to prepare food. An observation study published in 2018 done over a period of 9 year found that the diet quality of people with anxiety and depressive disorder is poorer. Furthermore, they also observed that the more severe and chronic the mental health symptoms, the poorer the diet quality (9). Altered food intake may impact the gut microbiome composition. Actually, studies have shown that patients living with major depressive disorder have different and less diversified gut microbiome than healthy subjects. Furthermore, patients with major depressive disorder have more bacterial with pro-inflammatory potential (4). Major depressive disorder is known to correlate with increases in pro-inflammatory cytokines, which can alter the HPA axis possibly accentuating depressive symptoms (4).


There is no proof of causal relation in human study between depression and gut microbiome, but one was found in animal models. Germ-free mices who received a fecal transplant from a patient with major depressive disorder developed a depression and anxiety symptoms (10). Here, the only intervention done was the fecal transplant and because the mice were germ-free, the only possible cause for the development of mental health symptoms was the bacteria received from a patient with major depressive disorder. This showed a direct link between the gut microbiome and development of depression (10). Other studies in animal models also observed increased inflammation, reduce microbiome diversity and depressive behaviours in mices, germ-free and regular, who received a fecal transplant from a patient with major depressive or anxiety disorder (4).


Regarding other mental health diseases, such as schizophrenia, bipolar disease, addiction and the autism spectrum disorder, studies have shown significant differences in the diversity of bacteria between patients with these mental health conditions and healthy control (4). For instance, a reduced abundance of the beneficial bacteria Bifidobacterium with an increased abundance of potentially pathogenic and pro-inflammatory bacteria has been observed in several studies for children with autism spectrum disorder (4). Another example with schizophrenia is the higher prevalence of pro-inflammatory group of bacteria compared with healthy control. These mental health diseases have complex etiology and more research will be needed to better understand the implication of gut microbiome, but these observations might be a piece of the puzzle and open doors to new areas of treatment (4).


Happy Gut Happy Life? Can having a healthy gut microbiome actually help with mental health?

While there's a growing body of evidence for the implication of the gut microbiome in mental health, telling somebody living with depression to simply fix their gut to feel better would be oversimplifying the situation (and indeed, inappropriate). Right now, there's no clear definition of what a '' depressive '' or even a healthy gut microbiome is. However, the richer and diversified the microbiome is, the better it is. How can we have a rich and diversified microbiome? A diversified diet rich in fibre with whole foods, such as vegetables, fruits, legumes and whole grains is the best way to ensure a good microbiome diversity. As previously mentioned, healthier diets are associated with better mental health outcomes. Other health indicators are also associated with a diversified gut composition, such as physical activity and sleep (4). Improving all these areas might definitely help with overall health and also to preserve a healthy gut microbiome.


Conclusion

It's an excited time for the area of the gut-brain-axis, more knowledge is gained every day around this topic! While many questions still remain unanswered, having a healthy lifestyle, including a balanced diet, will be beneficial to keep a diversified and rich microbiome and may help with mental health too! If you have any concerns regarding your diet, do not hesitate to gee see a registered dietitian!


Marie-Pier Pitre-D'Iorio, RD, B.Sc.Psy

Written by: Myriam Beaudry (B.Sc.Nutrition Student)

Thank you so much for this great and informative article :D


References

(1) Carabotti, M., Scirocco, A., Maselli, M. A., & Severi, C. (2015). The gut-brain axis : Interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology : Quarterly Publication of the Hellenic Society of Gastroenterology, 28(2), 203‑209.

(2) Latorre, R., Sternini, C., De Giorgio, R., & Greenwood-Van Meerveld, B. (2016). Enteroendocrine Cells : A Review of Their Role In Brain-Gut Communication. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 28(5), 620‑630. https://doi.org/10.1111/nmo.12754

(3) A Hole in the Stomach Provides Window into Digestion | Live Science. (2013). Consulté 22 février 2020, à l’adresse https://www.livescience.com/28996-hole-in-stomach-revealed-digestion.html

(4) Cryan, J. F., O’Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., Guzzetta, K. E., Jaggar, M., Long-Smith, C. M., Lyte, J. M., Martin, J. A., Molinero-Perez, A., Moloney, G., Morelli, E., Morillas, E., … Dinan, T. G. (2019). The Microbiota-Gut-Brain Axis. Physiological Reviews, 99(4), 1877‑2013. https://doi.org/10.1152/physrev.00018.2018

(5) O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural Brain Research, 277, 32‑48. https://doi.org/10.1016/j.bbr.2014.07.027

(6) Campbell, J., Berry, J., & Liang, Y. (2019). Chapter 71—Anatomy and Physiology of the Small Intestine. Dans C. J. Yeo (Éd.), Shackelford’s Surgery of the Alimentary Tract, 2 Volume Set (Eighth Edition) (p. 817‑841). https://doi.org/10.1016/B978-0-323-40232-3.00071-6

(7) Leitão-Gonçalves R, Carvalho-Santos Z, Francisco AP, Fioreze GT, Anjos M, Baltazar C, Elias AP, Itskov PM, Piper MDW, Ribeiro C. Commensal bacteria and essential amino acids control food choice behavior and reproduction. PLoS Biol 15: e2000862, 2017. doi:10.1371/journal.pbio.2000862.

(8) Alcock, J., Maley, C. C., & Aktipis, C. A. (2014). Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays, 36(10), 940‑949. https://doi.org/10.1002/bies.201400071

(9) Gibson-Smith, D., Bot, M., Brouwer, I. A., Visser, M., & Penninx, B. W. J. H. (2018). Diet quality in persons with and without depressive and anxiety disorders. Journal of Psychiatric Research, 106, 1‑7. https://doi.org/10.1016/j.jpsychires.2018.09.006

(10) Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., Zeng, L., Chen, J., Fan, S., Du, X., Zhang, X., Yang, D., Yang, Y., Meng, H., Li, W., Melgiri, N. D., Licinio, J., Wei, H., & Xie, P. (2016). Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Molecular Psychiatry, 21(6), 786‑796. https://doi.org/10.1038/mp.2016.44

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Marie-Pier Pitre-D'Iorio

B.Sc. Psychology | B.Sc. Psychologie      

Registered Dietitian | Diététiste Professionelle