Brain-Gut-Microbiota Axis: There are approximately 10¹³-10¹⁴ microbes in the human being. Microbial cells are 10 times more numerous than human cells in the human body such that 90% of the cells in the human body are microbes.  Approximately 500-1000 microbial species occupy the human gut. The microbes perform vital functions for the human host. Without these microbes, the gut immune system fails to develop. Harmless bacteria (called commensal bacteria) are needed to compete with harmful bacteria for space and nutrients. Commensal bacteria degrade dietary fiber into short-chain-fatty-acids which then can be absorbed. Commensals are required for the absorption of vitamin K and B (Bailey et al., 2011; Dinan &Cryan, 2012).

The composition of the microbiota community is important because some species are highly inflammatory whereas other species are anti-inflammatory. In almost all human cells there are pattern recognition receptors that recognize “foreign” molecules. Some foreign molecules belonging to bad bacteria will result in inflammation which gets communicated by the vagus nerve to the brain resulting in negative moods (anxiety and depression as discussed in the next section). Other foreign molecules associated with good commensal bacteria activate alternative pattern recognition receptors that lead to the release of white-blood-cell hormones (such as interleukin-10) that counter inflammation (Dinan, Stanton, & Cryan, 2013: Smits, et al., 2005), although the mechanism for how this is accomplished are still being worked out (Geuking, McCoy, & Macpherson, 2011). The IL-10 (white-blood cell hormone) protects the human gut from any aggressive inflammatory response that might be evoked by a bad bacteria.

The Composition of the Gut Microbiota Influences Behavior. Biologists who work with mice know that there are major strain differences in innate anxiety levels. Some mice strains are very wary of the novel and readily freeze. The skittish strains are prone to trepidations and rarely venture forth. Other strains are fearless and outgoing. While a good guess might have been that the mice differ in some aspect of the nervous system, turns out that what accounted for the difference between the species was the bacteria that they harbor in their guts. When researchers transferred the bacteria of the skittish mice into the intrepid mice, the intrepid mice exhibited anxious behavior and showed a decrease in BDNF, a protein required for optimal brain health, in their hippocampi. When researchers did the reverse fecal transplant experiment, transferring the intrepid mice microbiota into the skittish mice, the skittish mice became daring and showed an increase in BDNF in their hippocampi (Collins, Kassam, & Bercik, 2013). There were genetic differences between the skittish and intrepid mice driving behavioral differences.   But, the genes had to do with differences in the immune systems not the neurotransmitters. Immune system differences can determine which bacterial species are eliminated and which are invited to stick around.

The composition of the gut microbiota determines more than depression and anxiety levels. Gut microbiota influence appetite, obesity levels, insulin resistance (type 2 diabetes), and memory. In a dramatic demonstration, researchers transferred the gut microbiota from the obese mice to the thin mice. The thin mice then got fat, even though they had not increased their calorie consumption (Turnbaugh et al., 2006).

Factors that Influence the Composition of the Microbiota. Not surprisingly antibiotics can drastically alter the composition of the microbial community in the gut. When antibiotics are used to eradicate pathogens in some part of the body, the friendly gut bacteria who keep the nasty bacteria in check are wiped out. A relatively common occurrence these days is that after a course of antibiotic treatment, Clostridium difficile, a really nasty bacteria, takes over in digestive tract; it’s hard to get rid of. These days, fecal transplants from a healthy donor are sometimes provided. The other two major influences on microbiota composition are stress and diet.

Stress Can Alter Microbiota Composition and Behavior.

Stressors will increase the release of stress hormones in the gut which will then alter the microbial colonies which will then provoke systemic inflammation (Bailey et al., 2011; Bangsgaard Bendtsen et al., 2012). (Systemic inflammation means that inflammatory, white-blood-cell hormones are increased in blood.) Beyond changing the colonies of microbiota in the gut, stress will also alter the tight connections between the cells lining the gut so the lining becomes more permeable to pathogens and to secretions from these pathogens, further contributing to systemic inflammation (Kiliaan et al., 1998).

Diet Is a Major Factor for Determining Microbiota Composition.  Eating fermented foods such as sour kraut and yogurt is good strategy for encouraging the colonization of good microbes in the gut. Fermented food substance are called probiotics.   Fermented foods contain the good bacteria. For increasing good bacteria in gut, there’s also the prebiotic strategy (which will be referred to later in reference to why eating apples is good). Rather than consuming beneficial bacteria directly, prebiotics is about consuming dietary nutrients that will promote the survival of beneficial microbes.

A number of studies have found that administration of the species of bacteria found in yogurt decrease anxiety and depressive behaviors (Bravo et al. 2011; Messaoudi et al., 2011). In animals, probiotics are also protective against the development of anxiety in responses to stressors (Cryan & O’Mahoney, 2011). In humans, probiotics narrowed the differences between high and low anxious subjects on stress hormones in the urine (Martin et al., 2009) and decreased anxiety and depression and reduced levels of the stress hormone cortisol in blood (Benton, Williams, & Brown, 2007; Messaoudi et al., 2011; Rao, et al., 2009). Consumption of probiotics decreased social anxiety in those scoring high on a measure of neuroticism (Hilimire, DeVylder, & Forestell, 2015). Additionally, Tillisch et al. (2013) showed that consumption of probiotics resulted in a reduction in activity in the insula while viewing emotionally evocative pictures and resulted in an increase in regulatory control over areas of the brain that respond to emotion.

While probiotics and prebiotics can potentially influence microbiota composition so that distress (anxiety and depressive behaviors) is reduced, other dietary factors will probably reverse the effect. Consequently attending to the entire diet is necessary if a positive effect is to be achieved.

Encouraging the wrong type of microbes. Generally, high saturated fat and refined sugar promote inflammatory microbes in the gut (Magnusson, Hauck, Jeffrey, Elias, Humphrey, Nath, Perrone, & Bermudez, 2015; Ohland et al., 2015; Trunbaugh et al., 2009).  However, the bottom line is likely to be more nuanced than merely saying that a particular molecule is good or bad. Spreadbury (2012) suggests that it is not just saturated fats or carbohydrate molecules that should be considered but rather whether these molecules are consumed in the context of high fiber. Thus, carbohydrates consumed in plant fiber might have a different impact than pure glucose. In fact, consumption of high fiber foods (apples) change microbiota composition in animal studies (Koutsos, Tuohy, Lovegrove, 2015).   Various bacteria live on fiber and thus eating fruit with fiber is a prebiotic strategy for increasing good bacteria.

Artificial sweeteners have also been shown to alter gut microbial communities in undesirable ways (Suez et al., 2014). Atypical antipsychotics also alter the microbiota in negative ways (Dinan, Stanton, & Cryan, 2010).

Chemicals that extend the shelf-life of foods. The food industry adds detergent-emulsifiers to many processed foods. (Most ice creams are loaded.) Several of these common emulsifiers (carboxymethylcellulose and polysorbate-80) were tested on mice in research conducted by Chassaing et al. (2015). The emulsifiers changed the composition of microbiota to less friendly species. With the change in microbiota composition, the protective mucus layer lining the gut was eroded, bacteria clung to the cells lining the gut, and the gut lining allowed invasion into the blood stream. Of course, the immune system rapidly responded to the presence of the bacteria and bacterial products. The results were low grade systemic inflammation, more insulin insensitivity, and weight gain. The authors of the study speculated that common food additives may be contributing to the rise in inflammatory bowel disease, diabetes, and obesity. The authors did not measure changes in behavior, but given the research cited here, it’s a good bet that behavioral changes might have been found.

The serotonergic, anti-panic neurons connection. The “old-friends” hypothesis has been in the literature for a while now. The idea is that formerly common dietary bacteria such as Mycobacterium vaccae (common in human feces used as fertilizer in some parts of the world) induce the production of anti-inflammatory hormones (IL-10). IL-10 tames inflammation such that allergies and inflammatory bowel diseases are less likely (Rook & Lowry, 2008). Additionally, M. vaccae induces a cluster of serotonergic neurons, in the interfasicular part of the dorsal raphe, which are anti-panic neurons (Lowry et al., 2007). Lowry et al. placed M. vaccae under the skin or into the lungs and showed that mice displayed less anxiety.   Administering M. vaccae orally also decreases anxiety associated behaviors and improves memory (Matthews & Jenks, 2013). Recently, Lowry et al. (2015) fed mice M. vaccae and then exposed them to a larger, more aggressive animal. Rather than succumbing to the aggressor, the M. vaccae pretreated mice fought back. In another test of the anti-anxiety impact of M. vaccae, Lowry showed that fearful responses are unlearned (extinguished) much more readily in mice treated with M. vaccae. Feeding with M. vaccae has been characterized as a way to vaccinate against PTSD (Reardon, 2015).

It should be noted here, that M. vaccae is an aerobic (oxygen requiring) microbe and thus could not live for very long in the gut. However, its cell membrane contains molecules that are recognized by the “pattern recognition receptors”. Signaling through the pattern recognition receptor is the mechanism for the increase in the anti-inflammatory hormone, IL-10.

Clarification on Serotonin. It is important to recognize that serotonin is just another neurotransmitter in the brain. It is used in both anxiety inducing and anxiety reducing circuits. (There are distinct sets of connecting neurons.) Thus, the above should not be interpreted to imply that increasing serotonin is necessarily good or bad, as is sometimes implied by the simplistic story that serotonin deficiency creates depression.   (The story on serotonin is reviewed in Chapter 2 of Neuroscience for Psychologists and Other Mental Health Professionals.)

The Microbiota Research Is Just Beginning. The importance of the gut microbiota for physical health, mood, and perhaps cognitive capacity is a recent discovery. There are still plenty of unknowns. Given that so much of the American diet is based on processed foods, each food addictive needs to be interrogated to determine its impact on the microbes in the gut, general inflammation, and mood and behavior. Also each probiotic in fermented foods needs to be evaluated. Preliminary research suggests they are not all the same. However, the implications of this research are apparent. In the future, those with depression might conceivably be treated with fecal transplants from happy people. But then, it just might be easier to eat lots of nut, fruits and vegetables and avoid the processed foods and artificial sweeteners and start enjoying yogurt (the stuff without the high fructose corn syrup).

Bailey, M. T., Dowd, S. E., Galley, J. D., Hufnagle, A. R., Allen, R. G., & Lyte, M. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain, Behavior, & Immunity, 25(3), 397-407.

Bangsgaard, Bendtsen, K. M., Krych, L., Sorsen, D. B. et al. (2012). Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse. PLoS One, 7, e46231.

Benton, D., Williams, C., & Brown, A. (2007). Impact of consuming a milk drink containing a probiotic on mood and cognition. European Journal of Clinical Nutrition, 61, 355-361.

Bercik, P., Denou, E. Collins, J., Jackson, W., Lu, J., Jury, J. et al. (2011). The intestinal microbiota affect central levels of brain derived neurotropic factor and behavior in mice. Gastroenterology 141, 599-609.

Bercik, P., Park, A. J., Sinclair, D., Khoshdel, A., Lu, J., Huang, X. et al. (2011). The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterology and Motility, 23, 1132-1139.

Bruce-Keller, A. J., Salbaum, J. M., Luo, M., Blanchard, E., Taylor, C. M., Welsh, D. A., & Berthould, H-R. (April 1, 2015). Obese-type gut microbiota induce neurobehavioral changes in absence of obesity. Biological Psychiatry, 77 (7), 607-615.

Chassaing, B., Koren, O., Goodrich, J. K., Poole, A. C., Srinivasan, S., Ley, R. E., & Gewirtz, A. T. (2015). Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature.

Collins, S. M., Kassam, Z., & Bercik, P. (2013). The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications. Current Opinion in Microbiology, 16, 240-245.

Cryan, J. F., & O’Mahony, (2011). The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterology, 23, 187-193.

Dinan, T. G., Stanton, C., & Cryan, J. F. (2013). Psychobiotics: a novel class of psychotropic. Biological Psychiatry, 74, 720-726.

Geuking, M. B., McCoy, K. D., & Macpherson, A. J. (2011). The continuum of intestinal CD4+ T cell adaptations in host-microbial mutualism. Gut Microbes, 26, 353-357.

Hilimire, M. R., Devylder, J. E., & Forestell, C. A. (June 2015). Fermented foods, neuroticism, and social anxiety: An interaction model. Psychiatric Research, 228 (2), 203-208.

Kiliaan, A. J., Saunders, P. R., Bijlsma, P. B., Berin, M. C., Taminlau, J. A., Groot, J. A., Perdue, M. H. (1998). Stress stimulates transepithelial macromolecular uptake in the rat jejunum. American Journal of Physiology: Gastrointestinal and Liver Physiology, 275, G1037-G1044.

Koutsos, A., Tuohy, K. M., & Lovegrove, J. A. (2015). Apples and cardiovascular health—is the gut microbiota a core consideration? Nutrients, 7 (6), 3959-3998.

Magnusson, K. R., Hauck, L., Jeffrey, B. M., Elias, V., Humphrey, A., Nath, R., Perrone, A., & Bermudez, L. E. (2015). Relationship between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience, 300, 128-140.

McKeran, D. P., Fitzgerald, P., Dinan, T. G., & Cryan, J. F. (2010). The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat. Neurogastroenterology and Motility, 22, 1029-1035.

Messaoudi et al. (2011). Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition, 105, 755-764.

Ohland, C. L., Pankiv, E., Baker, G., & Madsen, K. L. (2015). Western diet-induced anxiolytic effects in mice are associated with alterations in tryptophan metabolism. Nutritional Neuroscience, doi: 10.1179/1476830515Y.0000000034

Rao, A. V., Bested, A. C., Beaulne, T. M., Katzman, M. A., Iorio, C., Berardi, H. M., & Logan, A. C. (2009). A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathology, 1, 6.

Rook, G. A., & Lowry, C. A. (2008). The hygiene hypothesis and psychiatric disorders. Trends in Immunology, 29 (4), 150-158.

Reardon, S. (12 June, 2015). Vaccine hope for post-traumatic stress: development of anxiety and fear alleviated by manipulating immune system in rodents. Nature News.

Salvin, J. (2013). Fiber and prebiotics: mechanisms and health benefits. Nutrients, 5, 1417-1435.

Smits, H. H., Engering, A., van der Kleij, D., de Jong, E. C., Schipper, K., van Capel, T. M. M., Zaat, B. A. J., Yazdanbakkish, M., Wierenga, E. A., van Kooyk, Y. T., & Kapsenberg, M. L. (2005). Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. Journal of Allergy and Clinical Immunology, 115, 1260-1267.

Spreadbury, I. (2012). Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity. Diabetes, Metabolic Syndrome, and Obesity: Targets and Therapy, 5, PMC34020009

Suez, J., Korem, T., Zeevi, D., Zilberman-Schapira, G., Thaiss, C. A., Maza, O., Israeli, D., Zmora, N., Gilad, S., Weinberger, A., Kuperman, Y., Harmelin, A., Kolodkin-Gal, I., Shapiro, H., Halpem, Z., Segal, E., & Elinav, E. (2014). Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, 514, 181-186.

Suez, J., Korem, T., Zilberman-Schapira, E., et al. (2015). Non-caloric artificial sweetners and the microbiome: findings and challenges. Gut Microbes, 6 (2), 149-155.

Tillisch, K., Labus, J., Kilpatrick, L. (2013). Consumption of fermented milk product with probiotic modulates brain-response to emotional pictures. Gastroenterology, 144, 1394-1401.

Turnbaugh, P. J., Ley, R. E., Mahowald, M. A. et al. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444, 1027-1031.

Turnbaugh, P. J., Ridaura, V. K., Faith, J. J., Rey, F. E., Knight, R., & Gordon, J. I. (2009). The effect of diet on the human gut microbiome: a metagenomics analysis in humanized gnotobiotic mice. Science Translational Medicine, 1: 6ra 14.