This blog post was written by Nina Gautam, an undergraduate student majoring in Human Biology and Society and sponsored by her graduate student mentor, Arielle Radin, a PhD student in Health Psychology.

How the microbiome, the collection of trillions of microorganisms that live in your gut, influences the brain has been a hot topic in popular science lately—from how the microbiome impacts healthy aging and mood to predicting one’s personality. Given all of the speculation in the media, I wondered what empirical evidence actually supports the link between the microbiome and psychological processes, focusing on implications for depression and anxiety. In this post I will explore the evidence linking the microbiome with depression and anxiety, associations with hallmarks of depression (cognitive control deficits, maladaptive emotional regulation), and explore a possible mechanism through which the microbiome exerts these psychological effects: the immune system.

There are numerous correlational studies that show an association between an altered gut microbiome and a diagnosis of major depressive disorder and/or general anxiety. Several animal studies have shown that taking probiotics decreases depressive and anxiety behaviors in rats (Evrensel & Ceylan, 2015), and even that a “depressive” microbiome can be transplanted into healthy rats to induce depressive-like behavior (Kelly et al., 2016). When looking at human studies, however, no specific strains of bacteria have been found to be significant related to depression (Cheung et al., 2019). Stress may also play a role in the link between depression and the microbiome: in addition to decreased depressive and anxiety symptoms, a reduction in perceived stress has also been found when taking probiotic supplements, leading to lower stress responses and HPA axis activation (McKean, Naug, Nikbakht, Amiet, & Colson, 2017).

In addition to altered stress responses, other key psychological processes that have been shown to be associated with depressive outcomes might be influenced by the gut microbiota. Cognitive theories of depression posit that deficits in cognitive control mechanisms (i.e., executive functioning), may confer risk for depression. A robust, diverse microbiome has been found to be crucial for normal cognitive development in infants and children (Emge et al., 2016), while less diverse microbiomes are characteristic of children with autism spectrum disorder (ASD) (Roman, Rueda-Ruzafa, Cardona, & Cortes-Rodríguez, 2018). In later stages of life, adults with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) present cognitive deficits when compared to healthy controls (Dancey, Attree, Stuart, Wilson, & Sonnet, 2009; Emge et al., 2016). Additionally, higher cognitive performance of healthy older adults has been found to be associated with certain phyla of bacteria (Manderino et al., 2017). There is evidence for a relationship between altered microbiome structure and normal cognitive functioning throughout one’s life, not just during developmental years. However, it also appears that the diversity of bacteria and some specific phyla of bacteria are more beneficial in preserving cognitive function than others.

Unfortunately, as with depression and anxiety, there haven’t been many studies done to isolate the specific mechanism through which the microbiome achieves these impacts on the brain. There is also contention over whether these changes in cognition appear in both neutral and negative/stressful situations or not. While one human study found probiotics to alter processing of emotion and sensation in neutral situations (Tillisch et al., 2013), another human study and preclinical study both found probiotic supplementation to alter behavior only in stressful situations, not neutral (Gareau et al., 2011; Papalini et al., 2019). More human clinical studies are needed to substantiate these findings and clarify the relationship between stress, the microbiome, and cognitive function. Additionally, the types of probiotics and cognitive tests used need to be considered; if some phyla are more beneficial than others, then the microbial composition of the probiotic supplementation is also important.

Another psychological process that has been linked with depression is emotion regulation. A hallmark feature of major depressive disorder is the use of maladaptive emotion regulation strategies (Joormann & Gotlib, 2010). Therefore, identifying possible links between the gut microbiome and emotion regulation will aid in our understanding of how the microbiome relates to depressive outcomes. Similar to cognitive functioning, a relationship between the microbiome and emotional regulation has been established, but the mechanisms through which they work are still mainly speculative. Only one study has linked visceral sensitivity to emotional dysregulation in the context of IBD and GI disorders, implicating vagal activity (Zvolensky et al., 2018). In determining specific methods of emotional regulation, there have mainly been clinical and human trials (which makes sense, since it would be quite difficult to assess how mice manage their emotions). However, in each of the studies, the emotional regulation tests employed were different, which could explain why these studies detected differences in the effects of supplementation. For example, while one study observed lower rumination and aggressive thoughts in subjects (Steenbergen, Sellaro, van Hemert, Bosch, & Colzato, 2015), another found a significant increase in positive affect and improved emotional attention (Bagga et al., 2018). There have also been some contradictory findings, including seeing improvements in emotion regulation of control groups over the course of the study in addition to the experimental groups (Messaoudi et al., 2011), and observing no changes in emotional regulation at all (Papalini et al., 2019). Thus, emotional regulation changes seem to be largely dependent on the emotional regulation tasks administered, and the method through which the changes are enacted is unknown. In order to gain more insight into the influence of probiotics on emotional regulation, more studies should examine areas of the brain involved in emotional regulation tasks alongside the supplementation of probiotics, as Tillisch et al. (2013) did in their experiment. This would allow for observation of the way different probiotic mixtures interact with the brain as well as how different emotion regulation tasks engage different areas of the brain.

Assessing the mechanisms underlying the gut-brain relationship in regards to depression and anxiety, there is evidence for three potential pathways: the HPA axis, the vagus nerve, and the immune system (Naseribafrouei et al., 2014).  Probiotic administration has repeatedly been shown to lower corticosterone levels in mice (the mouse equivalent of the human stress hormone cortisol), demonstrating a dampening of HPA axis responses in stressful situations (Peirce & Alviña, 2019). Mice given a vagotomy before receiving a fecal transplant from a mouse with a depressive phenotype did not exhibit depressive behaviors, indicating the vagus nerve is essential in gut-brain communication (Kelly et al., 2016). Additionally, increases in cytokines and gut permeability (possibly leading to endotoxemia) have also been observed in MDD patients, supporting the immune-mediated aspect of the relationship (Peirce & Alviña, 2019).

Inflammation has been implicated in the pathophysiology of many different diseases, from obesity to Lyme’s disease to depression. Chronic stress/allostatic load, the environment, lifestyle choices, and genetics all contribute to overall levels of inflammation in the body. Not surprisingly, the gut microbiome has also been implicated in contributing to inflammation. The microbiome has been pinned as responsible for maintaining the healthy epithelial barrier of the gut, which diminishes the ability of bacteria to exit the GI tract and get into the bloodstream (Sarkar, Amar; Harty, Siobhan; Lehto, Soili M.; Moeller, Andrew H.; Dinan, Timothy G.; Dunbar, Robin I.M.; Cryan, John F.; Burnet, 2018). This is because once they get into the bloodstream, microbes are sensed by immune cells as ‘foreign bodies,’ and elicit an immune response (Peirce & Alviña, 2019). In stressful situations, the permeability of the epithelium has been seen to increase, showing that ‘stress-induced endotoxemia’ is a very prominent pathway through which the gut communicates with the brain (Peirce & Alviña, 2019). This also provides somewhat of an explanation for altered microbiomes in stressful conditions, and why probiotic supplementation is effective at preventing those behavioral changes. The microbiome was also observed, however, to communicate in another way with the immune system: through microbial metabolites. Metabolites have been seen to interact with immune cells in a highly specific manner, exhibiting a unique bidirectional communication between the two (Schirmer et al., 2016).

The observations of gut alteration in depressed patients, inflammation as a byproduct of gut imbalance, and low-grade inflammation as a symptom of some forms of depression all lead to the assumption that depressive symptoms may be a side effect of immune activation triggered by lack of epithelial integrity (Sarkar, Amar; Harty, Siobhan; Lehto, Soili M.; Moeller, Andrew H.; Dinan, Timothy G.; Dunbar, Robin I.M.; Cryan, John F.; Burnet, 2018). However, this has not yet but been explicitly examined. Additionally, ‘sickness behaviors’ and other cognitive/emotional changes associated with common illnesses should be analyzed for their accompanying inflammation levels and the integrity of the gut. Clearly, the microbiome is highly involved in the activation of the immune system in both stressful and healthy situations, causing inflammation or communicating with the immune system in a variety of ways. Interrogating the link is the next step.

Given the evidence for the effects of the gut bacteria on the immune system, I wanted to dive deeper to explore evidence for the link between the microbiome and psychological processes, as mediated explicitly by the immune system. As we have repeatedly seen, although many studies postulate that the immune system may explain the link between the microbiome and psychological processes, it has seldom been experimentally tested thus far. Of the few studies that have been conducted, the results are contradictory. For example, one study found that decreased depression scores were not associated with reduced inflammation at all, despite probiotic supplementation, indicating that immune mediation cannot be directly attributed to psychological processes (Kazemi, Ali, Azam, & Djafarian, 2019). On the other hand, a preclinical study showed that probiotics did help reduce stress-related behavioral changes in rats by acting on specific immune cells, indicating the gut microbiome is important for buffering inflammatory stress responses (Bharwani, Mian, Surette, Bienenstock, & Forsythe, 2017). Therefore, individual bacterial strains in the microbiome seem to interact with the immune system to minimize inflammatory responses to stress, which translates psychologically to an increase in proactive coping methods. Unfortunately, no conclusions can be drawn about immune mediation of the gut-brain axis in neutral situations from the little data we have. This avenue clearly holds lots of potential for psychological processes, though, and deserves much more clinical attention and experimentation.

While the media’s fascination with the microbiome may change from day to day, most literature provides supporting evidence for the benefits of healthy, diverse microbiomes. Future studies should attempt to isolate individual pathways to determine which has the biggest effect on the gut-brain link, under what circumstances each is utilized, or how they interact and complement each other. Furthermore, the lack of identification of specific bacteria correlated with depression could be due to differences in function of bacteria, and their outputs, rather than the specific bacteria themselves (Cheung et al., 2019). A functional analysis of the depressed patients’ microbiomes may give better insight into what specific metabolites are missing, rather than searching for individual strains. Lastly, it is still unclear which comes first: onset of depression, or an altered microbiome. While preclinical trials have shown that once a depressive microbiome is created, it can be transplanted, but how does it occur in humans, over time, in real life, as they are reacting to the stressors of their everyday lives? 

References

Bagga, D., Reichert, J. L., Koschutnig, K., Aigner, C. S., Holzer, P., Koskinen, K., … Schöpf, V. (2018). Probiotics drive gut microbiome triggering emotional brain signatures. Gut Microbes, 9(6), 486–496. https://doi.org/10.1080/19490976.2018.1460015

Bharwani, A., Mian, M. F., Surette, M. G., Bienenstock, J., & Forsythe, P. (2017). Oral treatment with Lactobacillus rhamnosus attenuates behavioural deficits and immune changes in chronic social stress. BMC Medicine, 15(1), 1–14. https://doi.org/10.1186/s12916-016-0771-7

Cheung, S. G., Goldenthal, A. R., Uhlemann, A. C., Mann, J. J., Miller, J. M., & Sublette, M. E. (2019). Systematic review of gut microbiota and major depression. Frontiers in Psychiatry, 10(FEB). https://doi.org/10.3389/fpsyt.2019.00034

Dancey, C. P., Attree, E. A., Stuart, G., Wilson, C., & Sonnet, A. (2009). Words fail me: The verbal IQ deficit in Inflammatory Bowel Disease and Irritable Bowel Syndrome. Inflammatory Bowel Diseases, 15(6), 852–857. https://doi.org/10.1002/ibd.20837

Emge, J. R., Huynh, K., Miller, E. N., Kaur, M., Reardon, C., Barrett, K. E., & Gareau, M. G. (2016). Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease. American Journal of Physiology – Gastrointestinal and Liver Physiology, 310(11), G989–G998. https://doi.org/10.1152/ajpgi.00086.2016

Evrensel, A., & Ceylan, M. E. (2015). The Gut-Brain Axis : The Missing Link in Depression. Clinical Psychopharmacology and Neuroscience, 13(3), 239–244.

Gareau, M. G., Wine, E., Rodrigues, D. M., Cho, J. H., Whary, M. T., Philpott, D. J., … Sherman, P. M. (2011). Bacterial infection causes stress-induced memory dysfunction in mice. Gut, 60(3), 307–317. https://doi.org/10.1136/gut.2009.202515

Joormann, J., & Gotlib, I. H. (2010). Emotion regulation in depression: Relation to cognitive inhibition. Cognition and Emotion, 24(2), 281–298. https://doi.org/10.1080/02699930903407948

Kazemi, A., Ali, A., Azam, K., & Djafarian, K. (2019). E ff ect of prebiotic and probiotic supplementation on circulating pro- in fl ammatory cytokines and urinary cortisol levels in patients with major depressive disorder : A double-blind , placebo-controlled randomized clinical trial. Journal of Functional Foods, 52(44), 596–602. https://doi.org/10.1016/j.jff.2018.11.041

Kelly, J. R., Borre, Y., O’ Brien, C., Patterson, E., El Aidy, S., Deane, J., … Dinan, T. G. (2016). Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of Psychiatric Research, 82, 109–118. https://doi.org/10.1016/j.jpsychires.2016.07.019

Manderino, L., Carroll, I., Azcarate-Peril, M. A., Rochette, A., Heinberg, L., Peat, C., … Gunstad, J. (2017). Preliminary Evidence for an Association Between the Composition of the Gut Microbiome and Cognitive Function in Neurologically Healthy Older Adults. Journal of the International Neuropsychological Society, 23(8), 700–705. https://doi.org/10.1017/S1355617717000492

McKean, J., Naug, H., Nikbakht, E., Amiet, B., & Colson, N. (2017). Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis. Journal of Alternative and Complementary Medicine, 23(4), 249–258. https://doi.org/10.1089/acm.2016.0023

Messaoudi, M., Lalonde, R., Violle, N., Javelot, H., Desor, D., Nejdi, A., … Cazaubiel, J. M. (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(5), 755–764. https://doi.org/10.1017/S0007114510004319

Naseribafrouei, A., Hestad, K., Avershina, E., Sekelja, M., Linløkken, A., & Wilson, R. (2014). Correlation between the human fecal microbiota and depression. Neurogastroenterology and Motility, 26, 1155–1162. https://doi.org/10.1111/nmo.12378

Papalini, S., Michels, F., Kohn, N., Wegman, J., van Hemert, S., Roelofs, K., … Aarts, E. (2019). Stress matters: Randomized controlled trial on the effect of probiotics on neurocognition. Neurobiology of Stress, 10(October 2018). https://doi.org/10.1016/j.ynstr.2018.100141

Peirce, J. M., & Alviña, K. (2019). The role of inflammation and the gut microbiome in depression and anxiety. Journal of Neuroscience Research, (December 2018), 1223–1241. https://doi.org/10.1002/jnr.24476

Roman, P., Rueda-Ruzafa, L., Cardona, D., & Cortes-Rodríguez, A. (2018). Gut-brain axis in the executive function of austism spectrum disorder. Behavioural Pharmacology, 29(7), 654–663. https://doi.org/10.1097/FBP.0000000000000428

Sarkar, Amar; Harty, Siobhan; Lehto, Soili M.; Moeller, Andrew H.; Dinan, Timothy G.; Dunbar, Robin I.M.; Cryan, John F.; Burnet, P. W. J. (2018). The Microbiome in Psychology and Cognitive Neuroscience. Trends in Cognitive Neuroscience, 22(7), 611–636.

Schirmer, M., Smeekens, S. P., Vlamakis, H., Jaeger, M., Oosting, M., Franzosa, E. A., … Xavier, R. J. (2016). Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell, 167(4), 1125-1136.e8. https://doi.org/10.1016/j.cell.2016.10.020

Steenbergen, L., Sellaro, R., van Hemert, S., Bosch, J. A., & Colzato, L. S. (2015). A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain, Behavior, and Immunity, 48, 258–264. https://doi.org/10.1016/j.bbi.2015.04.003

Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., … Mayer, E. A. (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology, 144(7), 1394-1401.e4. https://doi.org/10.1053/j.gastro.2013.02.043

Zvolensky, M., Jardin, C., Farris, S. G., Kauffman, B., Bakhshaie, J., Garey, L., … Mayorga, N. A. (2018). Gut interpretations: how difficulties in emotion regulation may help explain the relation of visceral sensitivity with depression and anxiety among young adults with gastrointestinal symptoms. Psychology, Health and Medicine, 23(7), 840–845. https://doi.org/10.1080/13548506.2018.1455984