Updated on March 27, 2023
Many patients who struggle with anxiety spend years (or even decades) trying to find an approach 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 the therapy and the individual patient’s response. Psychotherapeutic approaches 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. 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 becoming increasingly 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, by regulating key physiological processes associated with anxiety. Still remaining to be fully elucidated is an understanding of 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 therapies, suggesting that probiotic, prebiotic, and butyric acid supplementation might be able to address select symptoms of anxiety.
Recent studies suggest there are two important ways in which bacterial activity in the gut facilitates 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 the various different bacterial strains residing in the gut microbiome directly determine which peptide-regulating signals are produced, suggesting that supplementation with certain bacterial strains would aid in the modulation of the gut-brain axis in ways that can beneficially address anxiety.
In a healthy gut, the resident bacteria produce a wide range of metabolites, including short-chain fatty acids, which are produced when certain bacterial strains metabolize fiber. These multifaceted short-chain fatty acids 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 the gut peptides associated with the gut-brain axis, including glucagon-like-peptide and leptin. These findings suggest that an imbalance of the bacteria that produce short-chain fatty acids might lead to disruptions in the gut-brain axis, which in turn contribute to the adverse symptoms of anxiety.
Any individual who has considered taking a probiotic supplement knows that the options on today’s market are practically endless when it comes to the number and combinations of available bacterial strains. This could be one reason the body of literature on the potential benefits of probiotic supplementation for various mental health conditions can only be described as mixed at best; and while some supplements seem to be beneficial for patients, others have no effect. Furthermore, it is unwise to compare studies of probiotic supplements that contain different bacterial strains. 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 addressing anxiety.
For example, in 2014 a group of researchers from University College Cork in Ireland conducted a study that suggested two strains of bacteria—Bifidobacterium longum 1714 and Bifidobacterium breve 1205—could address 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 humans. In the second 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 lower cortisol levels in the participants who had taken the probiotic supplements. Moreover, in subjective surveys, the 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.
A study from 2011 suggests that the bacterial strain Lactobacillus rhamnosus plays 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 strain could alter mRNA expression of GABA receptors in the brains of mouse models. GABA is an inhibitory neurotransmitter in the brain, and receptor levels are associated with anxiety symptoms. According to these researchers, these levels were altered in several different areas of the brain related to anxiety symptoms when the mice were administered 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 the vagus nerve likely plays a mechanistic role in the mediation of anxiety symptoms through the gut-brain axis. Therefore, this study not only suggests L. rhamnosus can be an effective probiotic therapy for anxiety patients, it also highlights the vagus nerve as a target for future research on possible therapeutics.
Probiotic supplementation that supports the health of the microbiome might not be the only way to target the gut-brain axis. There is also growing evidence that certain types of prebiotics offer specific benefits for anxiety patients. 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 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 address anxiety symptoms in mice, based on several well-established behavioral tests. In addition, fiber supplements were associated with lower levels of the pro-inflammatory markers commonly associated with anxiety, as well as lower levels of stress-inducing corticosterone. These findings suggest certain combinations of prebiotic fibers target the bacterial strains that play an essential role in the mediation of anxiety symptoms via the gut-microbiome axis, so they likewise could help alleviate anxiety symptoms, much like direct probiotic supplementation.
Based on the 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 to relieve anxiety symptoms. Therefore, some researchers and clinicians are considering the benefits of direct supplementation with short-chain fatty acids, such as butyric acid. This approach allows a butyric acid supplement to assume the role of the bacteria in the microbiome—that is, short-chain fatty acids are introduced into the gut, thus bypassing the step in which the bacteria metabolize fiber to produce these functional compounds. Instead of relying on bacteria to produce 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 thereby possibly modulate the biological processes that might benefit anxiety 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 does play an important role. There are already several probiotic strains that have been identified in the connection between the GI tract and the CNS, and supplementation with prebiotics and short-chain fatty acids might also exert beneficial effects in this regard. Although large-scale human studies are still lacking, clinicians and patients dealing with anxiety can harness this evidence to develop unique strategies for individuals 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.
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