Modern medicine has produced an astronomical number of benefits for Western society and the world. Thanks to the work of countless scientists and doctors, we can now easily survive diseases that once meant certain death. Likewise, advancements in agriculture mean that we can now produce greater amounts of more nutritious food than ever before. However, these benefits may come at an unexpected cost to our physical and mental health.

Human Immune Responses

To understand why, we must examine the human immune system. Our immune responses are regulated by a highly intricate network of cells, some of which are microorganisms living inside our body1. These minuscule creatures, such as certain species of bacteria, are not harmful; instead they co-evolved with mammals and contribute to our survival2. But due to improvements in medical treatments and cleanliness in general, we are no longer exposed to some microbes3, and some helpful organisms never make it into our immune system. Western diets no longer include many of the carbohydrates that these microorganisms use as food sources, which impairs their growth4. So, our immune systems seem to suffer regulatory deficiencies, particularly when managing responses to inflammation, which could produce worse symptoms of physical and mental disorders5-6.

Research has found that chronic stress-related disorders such as IBS (irritable bowel syndrome) and PTSD (posttraumatic stress disorder) are linked to distinct immune system deficiencies7-9. However, there is also evidence that trauma and stressors can cause changes to the gut microbiome10 (the collection of microorganisms living in the human body). It remains unclear whether disrupted immune system functioning causes these disorders or whether these disorders disrupt immune system functioning.

The Bacteria Connection

To better understand this relationship, Dr. Stefan Reber at the University of Ulm in Germany and his colleagues investigated how the bacteria Mycobacterium vaccae (M. vaccae) affected stress-related behaviors and neural circuitry in rats11. M. vaccae has been associated with improved immune system regulation in mammals12, so the researchers hypothesized that immunizing these rats with a heat-killed version of M. vaccae could lead to a healthier stress response .

In their study, the researchers found that rats who had been immunized with M. vaccae showed increased proactive coping in stressful social environments. Specifically, the rats showed decreased submission, flight, and avoidance behaviors when housed with a threatening male rat. They also tested rats on an "elevated plus maze," which is an elevated plus-sign with open-air arms. Exploring the arms of these mazes is stressful for rats, given the chance they may fall. The researchers found that the rats immunized with M. vaccae spent more time exploring the elevated arms of the maze than rats who had not been immunized, indicating that they experienced less stress in this environment. The results in two separate situations indicated that the immunized rats had an improved response to stress.

Gut Microbiome and Behavior

Next, the researchers examined how the immunization affected the body physically to discover how changing the gut microbiome affected behavior. They found that rats who had been immunized had altered gene expression in highly specific neural regions associated with stress coping strategies and stress resilience13. They also found that immunization seemed to prevent or reduce stress-related inflammation of the colon, which could reduce the symptoms associated with other physical or mental disorders14.

These findings provide extremely strong evidence that the gut microbiome plays an important role in the mammalian stress response. Not only did the injections of M. vaccae increase proactive coping to stressful situations, they also led to specific physiological changes in the brain and gut that increased the body's resilience to stress and trauma.

Major Implications

This study demonstrates that changes to the gut microbiome can produce significant changes in the stress response at the behavioral and neural levels. It also indicates that one might be able to increase resilience to stress by modifying the gut microbiome. These effects could inform treatments of chronic, anxiety, and stress-related disorders. In fact, the senior researcher involved in the study, Dr. Christopher Lowry, wants to test whether such an approach could help humans suffering from PTSD11.

The scientific community has taken note of this study. It was recognized by the Brain and Behavior Research Foundation, the largest non-governmental funder of mental health research in the United States, as one of the top 10 breakthroughs of 201615-16. This work could pave the way for a much more refined understanding of how the gut microbiome affects behavior, and importantly, it could lead to completely new forms of treatment to help both physical and mental disorders. Given the attention this study has received, we hope to see many new developments in 2017 and the coming years.

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Sources

1. Sonnenburg, E. D., & Sonnenburg, J. L. (2014). Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell metabolism, 20, 779-786.

2. Rook, G. A. W., Raison, C. L., & Lowry, C. A. (2014). Microbial 'old friends', immunoregulation and socioeconomic status. Clinical & Experimental Immunology, 177, 1-12.

3. Atherton, J. C., & Blaser, M. J. (2009). Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. The Journal of clinical investigation, 119, 2475-2487.

4. Von Hertzen, L., Beutler, B., Bienenstock, J., Blaser, M., Cani, P. D., Eriksson, J., ... de Vos W. M. (2015). Helsinki alert of biodiversity and health. Annals of medicine, 47, 218-225.

5. Eraly, S. A., Nievergelt, C. M., Maihofer, A. X., Barkauskas, D. A., Biswas, N., Agorastos, A., ... Baker, D. G. (2014). Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA psychiatry, 71, 423-431.

6. Hodes, G. E., Pfau, M. L., Leboeuf, M., Golden, S. A., Christoffel, D. J., Bregman, D., ... Russo, S. J. (2014). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proceedings of the National Academy of Sciences, 111, 16136-16141.

7. Sommershof, A., Aichinger, H., Engler, H., Adenauer, H., Catani, C., Boneberg, E. M., ... Kolassa, I. T. (2009). Substantial reduction of naive and regulatory T cells following traumatic stress. Brain, behavior, and immunity, 23, 1117-1124.

8. O'Donovan, A., Cohen, B. E., Seal, K. H., Bertenthal, D., Margaretten, M., Nishimi, K., & Neylan, T. C. (2015). Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biological psychiatry, 77, 365-374.

9. Cámara, R. J., Gander, M. L., Begré, S., Von Känel, R., & Swiss Inflammatory Bowel Disease Cohort Study Group. (2011). Post-traumatic stress in Crohn's disease and its association with disease activity. Frontline gastroenterology, 2, 2-9.

10. 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, and immunity, 25, 397-407.

11. Reber, S. O., Siebler, P. H., Donner, N. C., Morton, J. T., Smith, D. G., Kopelman, J. M., ... Lowry, C. A. (2016). Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proceedings of the National Academy of Sciences, 201600324.

12. Zuany-Amorim, C; Sawicka, E; Manlius, C; Le Moine, AL; Brunet, LR; et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nature medicine, 8, 625-629 (2002)

13. Loughridge, A. B., Greenwood, B. N., Day, H. E., McQueen, M. B., & Fleshner, M. (2013). Microarray analyses reveal novel targets of exercise-induced stress resistance in the dorsal raphe nucleus. Frontiers in behavioral neuroscience, 7, 37.

14. Graff, L. A., Walker, J. R., & Bernstein, C. N. (2009). Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflammatory bowel diseases, 15, 1105-1118.

15. University of Colorado Boulder. (2017, January 5). Study Linking Beneficial Bacteria to Mental Health Makes Top 10 list for Brain Research. CU Boulder Today. Retrieved from http://www.colorado.edu/today/2017/01/05/study-linking-beneficial-bacteria-mental-health-makes-top-10-list-brain-research

16. Brain & Behavior Research Foundation. (2016, December 28). The Brain & Behavior Research Foundation Names Top 10 Advancements & Breakthroughs in 2016 by NARSAD Grantees. Retrieved from https://bbrfoundation.org/news-releases/the-brain-behavior-research-foundation-names-top-10-advancements-breakthroughs-in-2016

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