Neurological

Understanding the Connection Between the Gut-Brain Axis and Anxiety: The Role of the Bacteria in the Microbiome

gut-brain axis and anxiety

patients who struggle with anxiety spend years (or even decades) trying to find a treatment option that truly works to address their symptoms, often without achieving durable relief. Indeed, studies show that the efficacy of psychotherapy and pharmacotherapy options can vary considerably, depending on both the nature of treatment and the individual patient’s response. Psychotherapeutic treatments like cognitive behavioral therapy, for example, often only partially alleviate symptoms, and many patients shy away from pharmaceutical drugs that carry side effects and fail to produce the desired outcomes for many patients. In order to develop more reliable therapies for patients with anxiety, scientists have spent decades trying to better understand the biological underpinnings of the condition. Although the question is far from resolved, it is clear that the gut-brain axis has a role in the mediation of symptoms.

The term “gut-brain axis” refers to the bidirectional connection between the gastrointestinal (GI) tract and the central nervous system (CNS). In recent years, researchers have discovered that the communication between these two systems has a direct impact on mental health, regulating key physiological processes associated with anxiety. However, scientists do not yet fully understand the biological mechanisms that link the GI tract and CNS to form the connections in the gut-brain axis that mediate symptoms of anxiety. One of the most promising proposals is that the activities of the bacteria in the microbiome play an essential role in the communication process. These findings have important implications for the development of future treatments, suggesting that probiotic, prebiotic, and short-chain fatty acid supplementation may contribute to the reduction of symptoms of anxiety in patients.

Bacterial Activity in the GI Tract and the Gut-Brain Axis

Recent studies suggest that there are two important ways in which bacterial activity in the gut may facilitate the communication that underpins the gut-brain axis: by interacting directly with peptides in the gut and by producing functional metabolites like short-chain fatty acids. There is a wide range of peptides present in the gut microbiome, and they communicate with the CNS by binding to immune receptors and the terminal of the vagus nerve, a peripheral nerve with a known connection to both anxiety disorders and inflammatory processes. Signals produced by the bacteria in the microbiome can directly regulate the concentrations of these peptides in the gut, which directly affects their communication with the CNS. According to the latest research, the proportions of different bacterial strains in the microbiome directly determine which peptide-regulating signals are produced, suggesting that supplementation with certain bacterial strains may aid in the modulation of the gut-brain axis in ways that reduce anxiety.

In a healthy gut, bacteria produce a wide range of metabolites, including short-chain fatty acids, which are produced when certain bacterial strains metabolize fiber. These multifaceted molecules have a variety of roles in key body processes, such as energy homeostasis and nutrient absorption. In addition, by acting as epigenetic regulators, short-chain fatty acids are involved in the production and activity of gut peptides with connections to the gut-brain axis, including glucagon-like-peptide and leptin. These findings suggest that an imbalance of bacteria that produce short-chain fatty acids may lead to disruptions in the gut-brain axis that can contribute to symptoms of anxiety.

Identifying Effective Probiotic Strains for Anxiety Treatment

Any patient who has ever considered taking a probiotic supplement knows that the options on today’s the market are practically endless when it comes to the number and combinations of available bacterial strains. This may be one reason the body of literature on the potential benefits of probiotic supplementation for anxiety and other mental health conditions can only be described as mixed at best; while some supplements seem to be beneficial for patients, others have no effect, and it is unwise to compare studies of probiotics containing different bacterial strains. In order to resolve the lack of clarity in this area of study, scientists are now conducting more specific studies on individual strains, a number of which have shown particular promise for patients with anxiety.

For instance, in 2014, a group of researchers from University College Cork in Ireland conducted a study suggesting that two strains of bacteria—Bifidobacterium longum 1714 and Bifidobacterium breve 1205—improved anxiety symptoms in mouse models, as measured by several different well-established behavioral tests for anxiety. Intriguingly, in a follow-up experiment conducted by researchers at the same university in 2016, these findings were verified in a small group of healthy patients. In the study, 22 healthy participants were subjected to an anxiety-inducing cold-pressor test, with and without supplementation of B. longum 1714. The researchers used resting encephalography to measure the participants’ output of cortisol (a stress hormone) under both conditions, and they observed reduced cortisol levels in the participants when they had taken the probiotic supplements. Moreover, in subjective surveys, participants reported perceiving lower levels of stress after taking the probiotic supplements. Based on these findings, the researchers concluded that Bifidobacterium strains could potentially be used as anti-anxiety therapeutics in the future.

Another study from 2011 suggests that the bacterial strain Lactobacillus rhamnosus may be playing an important role in the mediation of communication via the gut-brain axis in ways that directly impact anxiety levels. The researchers found that taking this supplement could alter mRNA expression of GABA receptors in the brains of mouse models. GABA is an inhibitory neurotransmitter in the brain, and receptor levels have been associated with symptoms of anxiety. According to the researchers, these levels were altered in several different brain areas related to anxiety symptoms when the mice were treated with L. rhamnosus, including the prefrontal cortex and the hippocampus. Importantly, in mice in which the vagus nerve had been removed, the characteristic symptoms of anxiety were not observed, which offers further evidence that this vagus nerve likely plays an imperative mechanistic role in the mediation of anxiety symptoms through the gut-brain axis. Therefore, this study not only suggests that L. rhamnosus may be an effective probiotic therapy for patients with anxiety, it also highlights the vagus nerve as a target for future research on possible therapeutics.

New Research on the Benefits of Prebiotics for Patients with Anxiety

Probiotic supplementation may not be the only way to target the gut-brain axis by supporting the health of the microbiome. There is also growing evidence that treatment with certain types of prebiotics may offer specific benefits for patients who struggle with anxiety. Prebiotics are fiber supplements that are indigestible by humans, but that feed certain strains of beneficial bacteria in the GI tract. In a groundbreaking study published in 2017, researchers found that supplementation with two types of prebiotics—fructooligosaccharides (FOS) and galacto-oligosaccharides (GOS)—can help modulate the gut microbiome in ways that affect the gut-brain axis. In a study in mouse models of anxiety, researchers found that prebiotic strains containing both FOS and GOS could reduce symptoms of anxiety in mice, based on several well-established behavioral tests. In addition, supplements were associated with reductions in pro-inflammatory markers that are commonly associated with anxiety, as well as lower levels of stress-induced corticosterone. These findings suggest that certain combinations of prebiotic fibers may target bacterial strains that play an essential role in the mediation of anxiety symptoms via the gut-microbiome axis, so they could help alleviate symptoms in patients, much like direct probiotic supplementation.

Assuming the Role of Bacteria in the Microbiome Through Short-Chain Fatty Acid Supplementation

Based on the new studies described above, it is clear that scientists have a growing sense of which bacterial strains are producing the essential metabolites that mediate the gut-brain axis. However, it is not yet entirely clear exactly which strains need to be replaced or nourished with prebiotics in order to relieve symptoms of anxiety. Therefore, some researchers and clinicians are considering the benefits of direct supplementation with short-chain fatty acids, such as butyric acid. This approach allows supplements to take on the role of the bacteria that make up the microbiome—that is, they introduce short-chain fatty acids into the gut, bypassing the step in which the bacteria metabolize fiber to produce the functional compound. Instead of relying on bacteria to produce the short-chain fatty acids, an oral supplement places them directly where they are needed: in the GI tract. As a result, short-chain fatty acids are readily available to mediate peptide levels and modulate biological processes that may reduce anxiety in patients.

Ultimately, even though the mechanisms through which the gut-brain axis mediates symptoms of anxiety have not been fully elucidated, there is little doubt that the gut microbiome plays an important role. There are already several probiotic strains that have been implicated in the connection between the GI tract and the CNS, and supplementation with prebiotics and short-chain fatty acids may also have anti-anxiety effects. Although large-scale human studies are still lacking, clinicians and patients dealing with anxiety may harness this evidence to develop unique treatment strategies for those who have not found success with traditional anti-anxiety therapies. The research community can also look forward to future studies that offer more mechanistic insight and real-world results related to the microbiome-mediated connection between the gut-brain axis and anxiety.

Foundational Medicine Review is committed to helping researchers, clinicians, and patients understand and act on the latest research related to complex, multi-faceted biological processes and health conditions. Join our mailing list today for more synthesis and analysis of the most innovative studies in the field.

Works Cited

Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, et al. 2016. Bifidobacterium longum 1714 as a translational psychobiotic: Modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational Psychiatry. 6(11):e939. https://www.ncbi.nlm.nih.gov/pubmed/27801892

Bourassa MW, Alim I, Bultman SJ, Ratan RR. 2016. Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health? Neuroscience Letters. 625:56-63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903954/

Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, et al. 2011. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAS. 108(38):16050-5. http://www.pnas.org/content/108/38/16050

Breit S, Kupferberg A, Rogler G, Hasler G. 2018. Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Frontiers in Psychiatry. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859128/

Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, et al. 2017. Targeting the microbiota-gut-brain axis: Prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biological Psychiatry. 82(7):472-87. https://www.ncbi.nlm.nih.gov/pubmed/28242013

Clapp M, Aurora N, Herrera L, Bhatia M, Wilen E, Wakefield S. 2017. Gut microbiota’s effect on mental health: The gut-brain axis. Clinics and Practice. 7(4):987. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641835/

Cuijpers P, Sijbrandij M, Koole SL, Andersson G, Beekman AJ, Reynolds CF. 2013. The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: A meta-analysis of direct comparisons. World Psychiatry. 12(2):137-48. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683266/

De Clercq N, Frissen MN, Groen AK, Nieuworp M. 2017. Gut microbiota and the gut-brain axis: New insights in the pathophysiology of metabolic syndrome. Psychosomatic Medicine. 79(8):874-9. https://www.ncbi.nlm.nih.gov/pubmed/28557822

Foster JA, Rinaman L, Cryan JF. 2017. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiology of Stress. 7:124-36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736941/

Lach G, Schellekens H, Dinan TG, Cryan JF. 2018. Anxiety, depression, and the microbiome: A role for gut peptides. Neurotherapeutics. 15(1):36-59. https://www.ncbi.nlm.nih.gov/pubmed/29134359

Savignac HM, Kiely B, Dinan TG, Cryan JF. 2014. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterology and Motility. 26(11):1615-27. https://www.ncbi.nlm.nih.gov/pubmed/25251188

Schnorr SL, Bachner HA. 2016. Integrative therapies in anxiety treatment with special emphasis on the gut microbiome. Yale Journal of Biology and Medicine. 89(3):397-422. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045149/

Vinolo MAR, Rodrigues HG, Nachbar RT, Curi R. 2011. Regulation of inflammation by short chain fatty acids. Nutrients. 3(10):858-76. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257741/

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