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The Gut-Brain Axis in Clinical Practice: Functional Approaches to Mental Wellness

Medically reviewed by 
The Gut-Brain Axis in Clinical Practice: Functional Approaches to Mental Wellness

Approximately half of the global population will suffer from a mental health disorder in their lifetime. The prevalence of mental health disorders has experienced a 50% increase over the last two decades, with approximately 300 million people suffering from anxiety and over 200 million suffering from depression. Beyond the personal toll, the financial burden is also substantial, with costs escalating from an estimated 2.5 trillion in 2010 to a projected 6 trillion by 2030. With advancements in medical research and an increased understanding of the dynamic connections between body systems, the gut-brain axis has emerged as a potential avenue to develop holistic approaches to mental health that could revolutionize how we perceive and address these disorders.


What is the Gut-Brain Axis?

The gut-brain axis, a complex communication network between the gastrointestinal and central nervous nervous systems (CNS), influences various aspects of physiological function and mental well-being. This communication network is bidirectional, involving a dynamic exchange of information between the gut and the brain through nervous system connections, hormones, neurotransmitters, and other signaling molecules.

The enteric nervous system (ENS) contains approximately 400-600 million neurons within the gastrointestinal tract's walls. It is often called the "second brain” because although it receives input from the CNS, it can also act independently due to local reflex circuits. The tenth cranial nerve's vagus establishes a direct link between the ENS and CNS. Signals from the gut are transmitted to the brain via the vagus nerve, such as information about the presence of nutrients, stretch of the gastrointestinal tract’s walls, and chemical signals released during digestion. In return, the brain also uses the vagus nerve to influence gut function, allowing it to modulate gastrointestinal activities like the secretion of digestive enzymes.

In addition to direct neural connections, the endocrine system and hormones modulate activity in the gut-brain axis. Gastrointestinal hormones, such as ghrelin, communicate hunger signals to the brain. In contrast, through the hypothalamic-pituitary-adrenal (HPA) axis, the brain releases hormones like cortisol that impact gastrointestinal motility, intestinal barrier function, and microbiome composition. 

The trillions of microorganisms that inhabit the gut, known as the microbiome, also play a crucial role in the gut-brain axis. These microorganisms are metabolically active and produce molecules such as short-chain fatty acids (SCFAs) and neurotransmitters that impact mood and brain function. The gut microbiota plays a role in maintaining the integrity of the intestinal barrier. Disruptions in this barrier can lead to the translocation of bacteria and their products, potentially influencing inflammation and affecting the CNS. Gut bacteria modulate immune system activity, hormone metabolism, and vagus nerve signaling.

The Gut-Brain Axis and Mental Health Disorders 

Imbalances in the gut-brain axis have emerged as a significant factor contributing to a spectrum of mental health disorders, including depression and anxiety. The gut microbiome, its metabolic byproducts like neurotransmitters, and immune responses, including inflammation, are all mechanisms through which the gut-brain axis profoundly influences mood and mental well-being.

The microbiome's composition is essential for maintaining health and influencing various physiological processes. Disruptions in this delicate balance, known as dysbiosis, have been found to have profound effects on mental health. Dysbiosis has multiple presentations, including a general loss of beneficial bacteria, an overgrowth in potentially pathogenic organisms, a decrease in the diversity of bacterial species, or conditions like small intestinal bacterial overgrowth (SIBO) where colon bacteria have migrated into the small intestine. Factors such as diet, medication use, and stress are all possible causes of dysbiosis. In dysbiosis, the changes to the microbiome composition can inhibit its ability to produce neurotransmitters and SCFAs, which ultimately impact the gut-brain axis.  Neurotransmitters, such as glutamate, GABA, and serotonin, influence mood, and imbalances have been associated with various mental health disorders, including anxiety and depression.  SCFAs produced by certain bacterial strains modulate neurotransmitter and neurotrophic factor production in the brain. Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), regulate the growth and maintenance of neurons, which are essential for the proper functioning of the nervous system. In mental health conditions, changes to the microbiome are commonly identified in which lower SCFA-producing strains of bacteria and higher levels of inflammatory gram-negative bacteria are seen. 

Dysbiosis can contribute to intestinal permeability, also known as leaky gut, in which the intestinal barrier breaks down, allowing substances such as bacteria and endotoxins to enter the bloodstream, triggering the immune system to release inflammatory messengers known as cytokines. Higher levels of cytokines in circulation can also increase the permeability of the blood-brain barrier (BBB), allowing inflammatory molecules to enter the brain and contribute to mood and cognition changes (12). 

Pro-inflammatory cytokines also activate the HPA axis, ultimately resulting in cortisol release. Cortisol functions as an inhibitory signal in the pro-inflammatory signaling pathway, but chronic hyperactivity or dysregulation in the HPA axis contributes to mood changes and can negatively impact gastrointestinal function. Approximately 40-60% of depressed patients present with disruptions in regular HPA axis activity. Cortisol readily travels into the brain, affecting neuroplasticity, growth, and differentiation of neurons. Prolonged HPA axis stimulation has been shown to change the structure of specific brain regions, like the hippocampus, prefrontal cortex, and amygdala. 

Functional Medicine Lab Testing

The gut-brain axis is a complex communication network influenced by a variety of imbalances. Functional medicine tests are instrumental in evaluating various aspects of this complex scenario, including gut health, inflammation, stress responses, and neurotransmitter levels. These assessments provide the foundation for creating personalized treatment plans to target the root causes of mental health disorders.

Cyrex Intestinal Permeability

The Array 2 by Cyrex Laboratories measures biomarkers related to intestinal barrier function, such as antibodies to zonulin and tight junction proteins. Elevations in these antibodies are indicative of intestinal permeability.

Blood-Brain Barrier 

Cyrex’s Array 20 measures antibodies against proteins related to the blood-brain barrier. Immune responses to these proteins can indicate increased blood-brain barrier permeability.

Organic Acids

The Organic Acids test (OAT) by Mosaic Diagnostics measures organic acids in the urine, which are byproducts of the body’s metabolic processes. The levels of these organic acids provide information about neurotransmitter imbalances, oxidative stress, and dysbiosis. 

Adrenal Testing

The Adrenocortex Stress Profile by Genova Diagnostics involves multiple salivary collections throughout the day to monitor the daily rhythm of cortisol. Cortisol levels naturally fluctuate throughout the day, and this test helps identify any abnormalities in this pattern indicative of HPA axis dysregulation. 

Micronutrient Testing

Certain nutrients play crucial roles in the production of neurotransmitters that regulate mood and brain function. Deficiencies in nutrients such as vitamin D, b vitamins, omega-3 fatty acids, magnesium, and zinc have been linked to mood disorders. Spectracell’s Micronutrient Test measures 31 vitamins, minerals, and other nutrients to assess nutrient status comprehensively.


C-reactive protein, or CRP, is produced in the liver in response to inflammation. High levels of CRP help assess the presence and severity of inflammation in the body. Higher levels of CRP are associated with both depression and anxiety. If CRP is elevated, additional problem-solving is required to identify the sources or triggers of that inflammatory response.


Functional Medicine Approach to the Gut-Brain Axis 

A functional medicine approach to mental wellness involves the recognition of the profound impact the gut-brain axis has on our mood. This approach identifies and addresses underlying imbalances that interrupt optimal gut-brain axis communication, considering factors such as diet, the microbiome, and stress. By promoting a healthy gut environment through dietary and lifestyle modifications, functional medicine supports a more balanced gut-brain axis, alleviating symptoms of mental health disorders and improving well-being.

Dietary Strategies for Supporting the Gut-Brain Axis

A balanced and nutrient-rich diet influences gut health, neurotransmitters, and inflammatory pathways, significantly impacting mood and mental health outcomes. Western diets are characterized by a deficiency in vital nutrients and an excess of processed foods, refined carbohydrates, salt, saturated fats, and trans fats. This dietary pattern can stimulate inflammation directly or indirectly through their influence on the microbiome composition. High sugar intake reduces microbial diversity and increases intestinal permeability, while plant-based, fiber-rich diets, such as a Mediterranean diet, foster beneficial commensal bacteria, inhibiting inflammatory responses. Focusing on nutrient density is essential for supporting neurotransmitter production, balanced stress responses, and providing neuroprotection. 

Diets rich in antioxidants, as found in fresh fruits and vegetables, can modify serotonin levels and are associated with a reduced risk of depression (30). The Mediterranean diet is low in saturated fats and rich in antioxidants, fibers, monounsaturated fats, omega-3 fatty acids, and probiotics, which helps reduce depressive symptoms (69) and decrease the risk of depression and anxiety (55). 

Prebiotics and probiotics, acquired either through dietary sources or supplements, aid in optimizing the microbiome composition. Prebiotics are non-digestible nutritional compounds, typically from carbohydrates or fiber, that serve as a nutrition source for beneficial gut bacteria to flourish. These compounds are found naturally in certain foods like fruits, vegetables, whole grains, and legumes or can be taken in supplemental form. Joint prebiotic supplements include inulin, fructooligosaccharides (FOS), resistant starch, and galactooligosaccharides (GOS). 

Probiotics are beneficial microorganisms found in fermented foods, such as yogurt, sauerkraut, and kimchi. Incorporating more fermented foods into your diet has been shown to improve microbial composition. Prebiotic and probiotic supplementation has also been found to enhance the microbiome's design and improve the symptoms of mental health conditions.

Lifestyle Modifications and Mind-Body Therapies

Stress negatively impacts the gut-brain axis through its effects on the nervous, endocrine, and immune systems. The parasympathetic nervous system (PNS) is known as the “rest and digest” portion of our nervous system in contrast to the sympathetic nervous system (SNS), the “fight or flight” portion, which is stimulated under stress. Mind-body therapies stimulate the body’s parasympathetic nervous system to counteract the adverse neuroendocrine effects of stress. As the PNS takes command, it fosters an environment conducive to optimal gut health by promoting efficient nutrient absorption, reducing inflammation, and maintaining a balanced gut microbiome. These techniques include mindfulness, meditation, yoga, deep breathing, and progressive muscle relaxation. Meditating for just 13 minutes a day for eight weeks can reduce negative mood and anxiety.

Sufficient, high-quality sleep plays a vital role in both physical and mental health. Evaluating good sleep includes the quality, quantity, and timing. Sleep disturbances, like insomnia, sleep deprivation, and disrupted sleep patterns, are associated with mood disorders. Sleep deprivation contributes to neuroinflammation and decreases important neurotrophic factors (70). It also changes the microbiome composition and increases inflammatory cytokines. The recommended sleep time for adults is between 7-9 hours. Some simple habits to implement to improve sleep quality include:

  • Sticking to a consistent sleep schedule.
  • Getting daytime natural light exposure.
  • Make sure the bedroom is cool, dark, and quiet.
  • Limiting screen exposure in the evenings.
  • Avoiding heavy meals and caffeine too close to bedtime.

Regular exercise and physical activity have been shown to influence the gut-brain axis positively. Physical activity is associated with changes in the gut microbiota composition, promoting the growth of beneficial bacteria and increasing SCFA production.  Exercise also directly influences brain health and mood by stimulating the release of neurotrophic factors like BDNF, increasing blood flow, and modulating endorphins and neurotransmitters. Physical activity has been shown to improve symptoms of anxiety and distress in both the general population as well as those diagnosed with mental health disorders. Adults who meet the standard recommendation for physical activity, the equivalent of 2.5 hours per week of brisk walking, are at lower risk of developing depression.

Integrative Treatments and Therapies 

Complementary therapies for mental health, including acupuncture, biofeedback, and herbal medicine, show potential in influencing the gut-brain axis and improve treatment outcomes. When integrated into personalized treatment plans, these therapies can enhance overall wellness by addressing the interconnected factors influencing mental health.


Acupuncture is a traditional Chinese medical practice that involves the insertion of thin needles into specific points on the body to stimulate energy flow or "qi." According to traditional Chinese medicine principles, disruptions in the flow of qi contribute to health issues. Acupuncture aims to restore balance to qi and promote the body's natural healing abilities. It has been used in the treatment of major depressive disorder, postpartum depression, and anxiety (2, 78). Proposed mechanisms for its positive effects on mood include endorphin release, regulating neurotransmitters, modulating the HPA axis, and balancing the autonomic nervous system response. 


Biofeedback is a therapeutic technique that involves monitoring and providing feedback about physiological processes in the body, such as heart rate, muscle tension, skin temperature, and other bodily functions. Biofeedback aims to help individuals gain greater awareness and control over these involuntary processes to improve physical and mental health. In a biofeedback session, sensors are attached to the body to measure physiological responses that are then displayed in real-time so individuals can observe and learn how their body responds to stimuli. In this manner, they can consciously learn to regulate these physiological functions through relaxation techniques. Biofeedback has been used as a treatment modality in both gastrointestinal disorders, like IBS, as well as mental health disorders like anxiety disorders and depression.

Herbal Medicine

Herbal medicine involves the use of plants or plant extracts for therapeutic purposes. Several herbs have been explored for their potential to support the gut-brain axis and mental health. 

Ashwagandha, or withania somnifera, is an herbal adaptogen, which means it helps the body to adapt to stress more effectively. It does so through a variety of mechanisms, including reducing cortisol levels and regulating neurotransmitters like dopamine, GABA, and serotonin. It has also been shown to inhibit the growth of potentially problematic bacteria in the gastrointestinal tract like Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Citrobacter freundii, and Klebsiella pneumoniae. 

Turmeric, or Curcuma longa, has potent anti-inflammatory, antioxidant, and neuroprotective properties. In the gut, curcumin has demonstrated the ability to modulate the composition of the microbiota, promoting the growth of beneficial bacteria while inhibiting the proliferation of harmful microbes. Moreover, curcumin's anti-inflammatory attributes contribute to a reduction in gut inflammation, mitigating symptoms in conditions like irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) (32, 35). Curcumin’s antioxidant effects in the brain safeguard neural cells from oxidative damage (5). 

Panax ginseng, commonly referred to as Asian or Korean ginseng, is a well-known adaptogenic herb that exerts beneficial effects on both gut health and mood. Through its adaptogenic influence on the HPA axis, ginseng can help prevent mood changes like depression and anxiety. Ginsenosides, active compounds in Panax ginseng, have neuroprotective effects, preventing oxidative damage to neural cells and contributing to overall brain health and function. They also exert positive impact on microbial composition in the gut.


The Gut-Brain Axis: Key Takeaways

Acknowledging the pivotal role of the gut-brain axis is paramount for enhancing mental wellness. A symbiotic relationship exists between gut health and mental health, emphasizing the need for a holistic and integrative approach to mental health care. Healthcare practitioners and patients alike should recognize the profound impact of factors such as diet, lifestyle, and the gut microbiome on neurological function and mood.

The information provided is not intended to be a substitute for professional medical advice. Always consult with your doctor or other qualified healthcare provider before taking any dietary supplement or making any changes to your diet or exercise routine.
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