Motivation and emotion/Book/2015/Digestive system and emotion

Digestive system and emotion:
What influence does the gut microbiome have on emotion?

Overview

This chapter has been developed to give the reader an overview of the digestive system and its relationship with the brain. Specifically, it will look at the relationship between gut microbiota living in the human digestive tract and the affect they have on our emotions, and subsequently our mood.

It has long been established that the brain can affect the gut. Mood is known to influence the properties of the gut, such as intestinal motor function and transit times (Moore, 2014). The feeling that many of us experienced as ‘butterflies in the stomach’ can be attributed to temporary changes in the gut that result from brief feelings of anxiety or excitement. These changes are not caused by microbes but rather the brain (Moore, 2014). It is only recently that studies have begun to look at this pathway in reverse, i.e., how the gut can influence the brain.

A great deal of research has been conducted over recent years that investigates this relationship and the potential implications and applications for various medical fields and treatments. In order to develop a deeper understanding of this topic this chapter will provide a definition of microbiomes and gut microbiota, a definition of emotions and mood disorders, and will also touch on a number of studies which have investigated the relationship between the two. Upon reading this chapter, it is hoped that you will achieve an understanding of the relationship between gut microbiomes and mood disorders, and an appreciation for the exciting potential applications that this research could have in the near future.

Questions to consider when reading this chapter:

What are microbiomes?
How is mood affected by gut microbiota?
What is the gut-brain axis?
What else is affected by our gut microbiota?

The digestive system

When food enters the mouth and begins its journey through the digestive system, interacting messages are sent to the brain. These messages contain loads of sensory, nutritive and other information. Brain regions such as the thalamus, amygdala, putamen and precuneus are activated when food is ingested (Holtmann & Talley, 2014). The brain integrates neural and hormonal signals that come from the stomach. The stomach has a distinct role to play in regards to ingestion of food. This function includes storing food and mechanically digesting it before it gradually empties into the duodenum. The stomach senses the composition of the gastric content. This information is then sent via the vagal nerve to the lateral hypothalamus and limbic system. Feelings of satiety and fullness are also attributed to the stimulation of these gastric tension receptors in the stomach (Holtmann & Talley, 2014). Current research would suggest that gastric afferents may influence mood, and studies on animals point towards the likelihood that gastric dysfunction could be a risk factor for mood disorders (Holtmann & Talley, 2014).

Brain-gut axis

The construct of the brain-gut axis describes the the complex bi-directional communication system that links the central nervous system and the gastrointestinal tract. The brain-gut axis plays an essential role in the maintenance of homeostasis. Dysregulation of the brain-gut axis has been linked to various disease states (Moloney, Desbonnet, Clarke, et al, 2013). In addition to facilitating central regulation of the digestive system and feelings of satiety and fullness, impairments in the brain-gut axis signalling is associated with gut inflammation, chronic abdominal pain and eating disorders (Moloney, Desbonnet, Clarke, et al, 2013). The gut-brain axis preceded any notion that gut microbiota could have a significant role in brain function (Moloney, Desbonnet, Clarke, et al, 2013).

Microbiomes

The terms microbiome and microbiota are essentially synonymous, thus for the purpose of this chapter they will be used interchangeably. Coined by Joshua Lederberg, the term microbiome is used to describe the ecological community of commensal, interdependent and pathogenic microorganisms that live within and on the human body (Lederberg & McCray, 2001; Luna & Foster, 2015). Lederberg was concerned that the importance of these microbiomes had all but been ignored as determinants of health and disease (Lederberg & McCray, 2001). Fortunately, this field of research has expanded in recent years.

It is estimated that the average human body consists of substantially more microbial cells than human cells, with these cells outnumbering human cells by more than ten to one. In fact, microbial cells account for approximately 1-3% of our total body mass (MacDougall, 2012). These microorganisms impact on the development and homeostasis of the human body, and alterations in the composition of the microbiota have serious implications for a multitude of metabolic and inflammatory illnesses (Shapiro, Thaiss, Levy, et al, 2014). The gut flora of adult humans can alter depending on a range of factors such as lifestyle, diet and age (O’Hara & Shanahan, 2006). These microbiota are not parasites, but are a collection of bacteria, viruses and fungi (Constandi, 2012).

Gut microbiome

The majority of microbiota live in the gut and form symbiotic relationships with the human body (Costandi, 2012). The human gut comprises the small intestine, large intestine, and the stomach (Costandi, 2012). The gastrointestinal tract contains almost 100 trillion bacteria from over 1000 discrete species (Annadora, Bruce-Keller, Salbaum, et al, 2015). The population of microbiota in the intestines is dense, here microbiota outnumber human cells by more than 100 to one (Alcock, Maley & Aktpis, 2014). This substantial microbe population is responsible for a number of pathological functions including nutrition and digestion, growth, inflammation, and immunity (Annadora, Burce-Keller, Salbaum, et al, 2015). The microbiota that reside in our gut release chemical signals that coerce the brain into craving particular foods (Bugs in the brain?, 2015). A review of the current research concluded that gut microbiota influence appetite, cravings and mood to ensure the foods we eat provide them with nutrients they need to survive. It is suggested that alterations to gut microbiota could be an effective in changing unhealthy eating habits (Bugs in the brain?, 2015).

Timeline of human gut microbiome development

Age has a significant impact on the composition of human gut microbiota. While in the womb, being a sterile environment, the fetus is largely free from these microbiota. However, once the baby is born colonisation begins, and is influenced by the mode of delivery, the infant diet, hygiene levels and medication (O'Hara & Shanahan, 2006).

Infancy (Birth - 1 year)

Colonisation of the infant gut begins at birth as delivery exposes the infant to bacteria. An infant's initial microbiome composition has a maternal signature. The microbiome of infants who have not yet been weaned off breastmilk is simple and is high in individual variability (Dinan & Cryan, 2012).

Early childhood to adulthood (1 - 65 years)

From one year of age a complex microbiome is established. This microbiome remains relatively stable throughout childhood and well into adulthood. Occasionally, factors such as infection, diet, and disease alter the composition of the microbiome, but generally, once the threat is diminished, the microbiome returns to its regular stable diversity (Dinan & Cryan 2012).

Old age (65 years +)

Core microbiota in elderly individuals are distinctly different to that of younger adults. Age related changes to the make up of the microbiota are though to be correlated to increased instances of adverse health effects in elderly humans (Dinan & Cryan, 2012).

Brain-gut-microbiota axis

The microbiome is now acknowledged as an active and highly influential contributor to the bi-directional communication network that is the brain-gut axis. This complex communication network includes the central nervous system, both the sympathetic and parasympathetic branches of the autonomic nervous system, the enteric nervous system, and the neuroendocrine and neuroimmune systems (Moloney, Desbonnet, Clarke, et al, 2013). The brain-gut-microbiota axis communicates via neuronal routes and also by humoural signalling molecules and hormonal components (Smythies & Smythies, 2014). There is also extensive communication via chemical signalling systems via the blood (Smythies & Smythies, 2014). This intricate communication network is powerful enough to influence our gastrointestinal and brain functions.

Emotions

Emotions are inherently complex, there is no universally agreed upon definition of what an emotion is. According to some theories, they are states of feeling that cause physical and psychological changes which then influence human behaviour (Myers, 2004). Physiologically, emotions are closely connected to the arousal of the nervous system (Cannon, 1927). Emotions are also considered to be the driving force behind both positive and negative motivation (James, 1884).

Two theoretical perspectives, behavioural and cognitive, endeavour to explain why we experience emotions (Myers, 2004; Reeve, 2015). The cognitive perspective suggests that emotions arise from a cognitive standpoint, which includes information processing, and social interaction. Three discrete types of cognition are distinguished: knowledge, appraisal and attribution. Of these three types, appraisal is considered a central construct explaining that our emotions are activated not by biological processes but by an individual’s appraisal of a situation of outcome (Myers, 2004). Alternatively, from a behavioural perspective, it is proposed that emotions occur due to biological processes (Myers, 2004; Reeve, 2015). Findings that suggest gut microbiota could have an implication in mood could lend support to a behaviouralist's interpretation of emotion.

For the purposes of this chapter, both depression and anxiety are considered to be emotions.

Mood disorders

Mental illnesses are said to arise from an overabundance of emotion (Simons, 2009). Simons (2009) believes that this overflow of emotion drives not only mood disorders, but also a range of other psychological problems such as phobias, traumas, hoarding behaviour, obsessive compulsions, borderline personality disorder, and also substance abuse. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM5) a mood disorder is diagnosed where disturbances in a person's mood or affect is hypothesised to be the primary feature (American Psychiatric Association [APA], 2013). Microbes are believed to be implicated in disorders such as depression, anxiety, dementia, and autism. Depression and anxiety have been the most thoroughly researched mood disorders with regards to their relationship with gut microbiota. Thus, for the purpose of succinctness, this chapter will focus predominantly on these two disorders.

Depression

Major depressive disorder (MDD), or clinical depression, is highly prevalent in the Western World. It is characterized by behavioural changes such as pervasive anhedonia, despair, poor concentration, decreased learning and memory ability, and withdrawal from the activities of daily life (Jorgenson, Hansen, Kyrch, et al, 2014). Environment and lifestyle have a significant part to play in nuerological disorders. Western diets are often high in saturated fat and sugar, yet low in omega-3 fatty acids. It is possible that the gut microbiota act as a mediator between diet and depression, as diet has been found to affect the bacterial composition of the gut (Jorgenson, Hansen, Krych, et al, 2014). Altered immune responses and an increase in inflammation have been noted in MDD (Smythies & Smythies, 2014). These stress-related reactions are moderated by pro-inflammatory cytokines that originate in the gastrointestinal mucosa and interact with the hypothalamic-pituitary-adrenal-gland stress axis. Diets that are high in refined sugar and saturated fat, low levels of physical activity, and smoking are all risk factors for MDD (Smythies & Smythies, 2014).

Pathogenic bacteria such as borrelia burgdorferi are known to cause Lyme disease, and two thirds of all sufferers are thought to also suffer from depression (Fallon & Nields, 1994).

Anxiety

Anxiety is an emotion that is characterized by an unpleasant state of internal turmoil. This state is often accompanied by nervous behaviour such as pacing, bodily pains and rumination. Sufferers experience subjective feelings of dread regarding future events, such as a feeling of imminent death. Anxiety is not the same as fear. Fear is a response to a real or perceived threat, where anxiety is an expectation of a future threat. According to the DSM5, anxiety disorders are characterized by pervasive feelings of anxiousness and fear (APA, 2013).

Much like depressive disorders, anxiety disorders have been found to be commonly associated with disturbances in gut microbiota (Micocka-Walus, Turnbull, et al, 2007). A number of experimental and human studies have found that a range of anxiety inducing, physiological and psychological stressors, such as confinement, extreme temperatures, crowded spaces, loud noises and academic examinations, can damage the normal microbiota in the gut (Bowe & Logan, 2011). The population of lactobaccillus and bifidobacteria species of microbiota reduces significantly when individuals are stressed (Bowe & Lowe, 2011).

Relevant theories and research

Probiotics

Probiotics are microorganisms that are thought to produce positive health benefits when consumed (Luna & Foster, 2015). This concept was first introduced by Russian zoologist Elie Metchnikoff. Microbiota in the gut are readily influenced by prebiotics, probiotics, anti-biotics, and fecal transplants (Alcock, Maley & Aktipis, 2014).

Specific changes in colon microbiota composition have been found to be associated with cognitive impairment in patients suffering from dysnfunction of the brain. Clinical studies into the use of probiotocs for treatment of this condition show that probiotics decrease anxiety and improve patient's mental outlook (as cited in Annadora, Bruce-Keller, Salbaum, et al, 2015).

Several studies using mice have demonstrated behavioural impacts when probiotics were administered, specifically, in regards to depressive and anxiety-like behaviours. Almost all of these studies have involved microbe species' lactobacillus and bifodobacteria. Administration of these probiotics, under various conditions, resulted in reduced anxiety-like and depressive behaviours in the mice (as cited in Luna & Foster, 2015).

Relationship between obesity, mood and gut microbiota

Unhealthy eating is a significant contributor to health problems, including obesity, diabetes, cancer, heart disease and sleep apnea (Alcock, Maley & Aktipis, 2014).

The prevalence of depressive-like symptoms is significantly higher in obese individuals than those of normal weight (Castanon, Luheshi & Laye, 2015). Obesity is also linked to dramatically increased risk of dementia and stroke (Annadora, Bruce-Keller, Salbaum, et al, 2015). Obesity is characterized by peripheral low-grade inflammation, believed to have originated from an increase in adipose tissue mass and changes in the composition of gut microbiota (Castanon, Luheshi & Laye, 2015).

Gut microbiota have been implicated in systemic and local inflammation (as cited in Castanon, Luheshi & Laye, 2014). The microbe lipopolysaccharide in particular has been linked to the onset and progression of obesity-related diseases and inflammation (as cited in Castanon, Luheshi & Laye, 2015).

*Figure 6.* Obese mouse and normal weight mouse.

Germ-free versus colonised mice

A number of comparative studies have been conducted on germ-free and colonised mice, initially to test the influence of microbiomes on intestinal physiology, and later to investigate the influence of microbiomes on mood.

The results of the first study demonstrated that the germ free mice had greatly enlarged cecums, reduced intestinal surface area, and were significantly more susceptible to infection (as cited in O'Hara & Shanahan, 2006). However, the reintroduction of intestinal microbiota to the germ-free mice was found to be sufficient in restoring their mucosal immune system (as cited in O’Hara & Shanahan, 2006).

Other studies conducted on mice, have discovered that germ-free mice respond to stress in an inflated manner and when experiencing feelings of stress release exaggerated amounts of corticosterone (Bailey & Coe, 1999). Again, when faecal matter from control mice were introduced to the germ-free mice, the stress response was partially reversed (Bailey & Coe, 1999). As such, it is believed that microbial gut composition is critical to the development of an appropriate stress response later in life (Dinan & Cryan, 2012).

In a separate study, Jorgenson, Hansen, Krych, et al (2014) found that mice who were fed diets high in saturated fat developed depressive-like behaviour. They considered changes in the gut microbiota to be a mediator (Jorgenson, Hansen, Krych, 2014).

*Figure 7.* Chocolate: some people are predisposed to love it, where others are not.

Chocolate preferences in humans

The microbiota that reside in our gut are under constant evolutionary pressure to manipulate our eating behaviours to increase their own fitness. They do this in two ways: (a) they generate cravings for specific foods that they specialise on, and (b) they induce dysphoria until we eat food that enhances their fitness (Alcock, Maley & Aktipis, 2014).

A study by Rezzi, Ramadan, Martin, et al, in 2007, found that secondary metabolites in the urine of 'chocoholics' differs substantially to that of chocolate-indifferent individuals (as cited in Moore, 2014). These researchers found that this wasn't residual left over from chocolate consumed by the 'chocoholics' as even without having eaten chocolate, the two groups differed in the composition of their intestinal microbiota in a way that specifically co-segregates with chocolate preference (Moore, 2014).

Interestingly, when those individuals who were chocolate-indifferent consumed chocolate they did not become more similar to the 'chocoholics' in terms of the secondary metabolites in their urine (Moore, 2014). This finding would suggest that for some individuals their gut microbiota may be predisposed to prefer, and thus induce cravings for, chocolate.

Brain maker

In his book 'Brain Maker: The Power of Gut Microbes to Heal and Protect Your Brain-for Life,' neurologist, Dr David Perlmutter, explores the quantity, quality, and composition of the bacteria in the human gut and their influence on the brain. Below is a table outlining the seven measures Dr Perlmutter recommends implementing in order to promote healthy gut bacteria (Mercola, 2015).

Table 1. Dr Perlmutter outlines seven keys for rehabilitating gut health, starting from birth.

1. Vaginal birth	If possible do not give birth via caesarian section. Babies delivered via C-section are at higher risk of obesity, type 1 diabetes, and food allergies, which are all inflammatory issues.
2. Breastfeeding	Breastfeeding provides the most appropriate nutrients fo rhte baby. Breastfeeding also affects the child's microbiome via bacterial transfer from skin contact.
3. Antibiotics	Changes to the microbiome tend to favour certain types of bacteria, for example firmicutes species. When present in excess fermicutes may increase the risk of obesity. Disinfectant products such as antibacterial soaps and hand gels also fall into this category and should be avoided.
4. Refined sugar and processed fructose	Sugar and high-frustose corn syrup act to increase the growth of pathogenic disease-causing bacteria, fungi and yest. Limiting the amount of refined and processed sugar in the diet is recommended. Dr Perlmutter believes that fructose promotes gut dysbioses and could be linked to permeability of the gut, or leaky gut, and inflammatory diseases like obesity.
5. Genetically engineered foods and pesticides	It is recommended that genetically engineered foods be avoided. The risk is that we are introducing foods that are genetically unlike anything that the human microbiome has ever encountered before and e don't yet know the consequences of ingesting such foods.
6. Probiotic foods	Dr Perlmutter recommends focusing on eating probiotic foods such as fermented vegetables, sauerkraut, kimchi, kefir, and kombucha. Broad-spectrum probiotic supplements are also recommended, especially after a course of antibiotics.
7. Prebiotic fibre	Consume plenty of prebiotic fibre. Be mindful that not all fibres are prebiotic. Ingestion of these fibres will allow your gut bacteria to flourish, which is the key to health, disease resistance and longevity.

Conclusion

It is clear from the above research that there is a relationship between the brain, the gut, and even the skin. This has been referred to as the gut-brain axis (Petra, Panagiotidou, Hatziagelaki, et al, 2015) and the gut-brain-skin axis respectively (Bowe & Logan, 2011). Some studies suggest there may be a gastrointestinal mechanism that is responsible for the overlap between depression, anxiety and skin conditions such as acne vulgaris. Acne vulgaris is a common skin condition which is frequently associated with depression and anxiety. Mental health impairment scores are higher among acne patients than those suffering other, non-psychiatric, ailments. There is also an indication that acne patients may be at higher risk for gastrointestinal distress (Bowe & Logan, 2011). This is further indication of the inter-relatedness of all the systems within the human body.

While it's not fully understood yet, there is also mounting evidence to suggest that the growth of cancerous tumors and bacterial communities are linked (Alcock, Maley & Aktipis, 2014). Continued research into the microbiota in and on our bodies could eventually lead to the discovery of cures for serious diseases such as cancer, diabetes, and obesity. The potential for metabolic microbes to act as moderators of our immune systems may be a challenge for future researchers when developing dietary interventions in immunity and inflammation (Shapiro, Thaiss, Levy, et al, 2014). However, the use of microbiota as a means of targeted intervention presents a very attractive and non-invasive possibility for future therapies. The findings and possible applications of the studies examined in this chapter are very exciting, especially with regards to the potential treatment of a range of illnesses and disorders. At this point in time causation cannot be professed, but it is apparent there is a strong correlation between our gut microbiota and the human brain. Researchers are making great headway with probiotics as treatments for mood disorders, however, a lot remains to be understood about this gut-brain relationship.

Suggestions:

Below are ways you can apply your new-found knowledge to improve your everyday life:

Limit your intake of saturated fat and high sugar foods
Increase your dietary intake of omega-3 fatty acids
Where possible eat fresh, non-processed produce
Limit your use of antibiotics
Limit your use of antibacterial cleaners and hand sanitisers

Test yourself

Were you paying attention? How much do you now know about the influence of microbiomes?

References

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Annadora, J., Bruce-Keller, A., Salbaum, J. M., Luo, M., Blanchard, E., Taylor, C. M., Welsh, D. A., Berthoud, H. R. (2015). Obese-type gut microbiota induce neurobehavioural changes in the absence of obesity. Biological Psychiatry, 77, 607-615.

Alcock, J., Maley, C. C., Aktipis, C. A. (2014). Is eating behaviour manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays, 36, 940-949.

Bailey, M. T., Coe, C. L. (1999). Maternal seperation disrupts the integrity ofthe intestinal microflora in infant rhesus monkeys. Developmental Psychobiology, 35,146-155.

Bowe, W. P., Logan, A. C. (2011). Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future?Gut Pathogens, 3(1), 1-11.

Bugs in the brain? (2015). General Practitioner, 1

Cannon, W. B. (1927) The James-Lange theory of emotion: A critical examination and an alternative theory. American Journal of Psychology, 39, 10-124.

Castanon, N., Luheshi, G., Laye, S. (2015). Role of neuroinflammation in the emotional and cognitive alterations displayed by anial models of obesity. Frontiers in Neuroscience, 9, 1-9.

Costandi, M. (2012). Microbes on your mind. Scientific American Mind, 23(3), 32

Dinan, T. G., Cryan, J. F. (2012). Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology, 37, 1369-1378.

Fallon, B. A., Nields, J. A. (1994). Lyme disease: A neuropsychiatric illness. The American Journal of Psychiatry, 151(11), 1571-1583.

Holtmann, G., Talley, N. J. (2014). The stomach-brain axis. Best Practice and Research Clinical Gastroenterology, 28, 967-979.

James, W. (1884). What is an Emotion? Mind, 9, 188-205.

Jorgensen, B. P., Hasen, J. T., Krych, L., Larsen, C., Klein, A. B., Nielsen, D. S., Josefsen, K., Hansen, A. K., Sorensen, D. B. (2014). A possible link between food and mood: Dietary impact on gut microbiota and behaviour in BALB/c mice. PLOS One, 9(8), 1-15.

Lederberg, J., McCray, A. T. (2001). ‘Ome sweet ‘omics – A genealogical treasury of words. Scientist 15, 8.

Luna, R. A., Foster, J. A. (2015). Gut brain axis: diet microbiota interactions and implications for modulation of anxiety and depression. Current Opinion in Biotechnology, 32, 35-41.

MacDougall, R. (2012). NIH human microbiome project defines normal bacterial makeup of the body. National Institute of Health. Retrievable from: http://www.nih.gov/news/health/jun2012/nhgri-13.htm

Mercola, J. (2015). Neurologist speaks out about the importance of gut health for prevention and treatment of “incurable” neurological disorders. Retrievable from: http://articles.mercola.com/sites/articles/archive/2015/05/17/gut-bacteria-brain-health.aspx

Micocka-Walus, A. A., Turnbull, D. A., Moulding, N. T., Wilson, I. G., Andrews, J. M., Holtmann, G. J. (2007). Controversies surrounding the comorbidity of depression and anxiety in inflammatory bowel disease patients. Inflammatory Bowel Diseases, 13(2), 225-234.

Moloney, R. D., Desbonnet, L., Clarke, G., Dinan, T. G., Cryan, J. F. (2014). The microbiome: stress, health and disease. Mamm Gerome, 24, 49-74.

Moore, A. (2014). Editorial: At the mercy of our microbes. Bioessays, 36, 905.

Myers, D. G. (2004). Theories of Emotion. Psychology: Seventh Edition. New York, NY: Worth Publishers.

O’Hara, A. M., Shanahan, F. (2006). The gut flora as a forgotten organ. European Biology Organisation. EMBO Reports, 7(7), 688-693.

Petra, A. I., Panagiotidou, S., Hatziagelaki, E., Stewart, J. M., Conti, P., Theoharides, T. C. (2015). Gutmicrobiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clinical Therapeutics, 37(5), 984-995).

Reeve, J. (2015). Understanding Motivation and Emotion. (6th Ed.). Wiley: Hoboken NJ

Shapiro, H., Thaiss, C. C., Levy, M., Elinav, E. (2014). The cross-talk between microbiota and the immune system: metabolites take center stage. Current Opinion in Immunology, 30, 54-62.

Simons, I. (2009). Why do we have emotions? Mental illness often results form excess emotion. The Literary Mind. Retrievable from: https://www.psychologytoday.com/blog/the-literary-mind/200911/why-do-we-have-emotions

Smythies, L. E., Smythies, J. R. (2014). Microbiota, the immune system, black moods and the brain - melancholia updated. Frontiers in Human Neuroscience, 8, 1-4

External Resources

TED Talk: "Rob Knight: How our microbes make us who we are" Rob Knight is a pioneer in studying human microbes.
TED Talk: "Jonathon Eisen: Meet your microbes" Jonathan Eisen studies the ecology and evolution of microbial communities, and their co-evolution with their hosts.
The Gastrointestinal Society of Australia
The Human Microbiome Project

	Increased anxiety-like and depressive symptoms
	Decrease in anxiety-like symptoms, but increase in depressive symptoms
	Decreased anxiety-like and depressive symptoms
	No change in anxiety-like and depressive symptoms

	True
	False

	True.
	False.

	True.
	False.