The concept of the gut as the “second brain” first emerged with the discovery of the enteric nervous system (ENS) in the gastrointestinal (GI) tract. The ENS has its own extensive network of neurons that can function somewhat independently of the central nervous system (CNS), controlling processes like the movement of food through the GI tract, digestive enzyme secretion, and regulating blood flow. This concept garnered even more momentum as researchers explored the bidirectional communication, known as the “gut-brain axis,” that exists between the gut and the CNS. 

Gut health issues are linked to the development of psychiatric, neurodevelopmental, neurological, and cognitive diseases, underscoring the importance of this axis. Statistics show that approximately 2 out of every 3 Americans will experience some level of cognitive decline by age 70. In addition, it's estimated that anxiety will affect around 30% of individuals, while approximately 20% will contend with mood disorders during their lifetime. The gut-brain axis serves as an important avenue for interventions and therapies to help optimize cognition and improve mental health.

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The Intricacies of the Gut-Brain Connection 

The ENS is the largest and most complex unit of the peripheral nervous system, containing approximately 400-600 million neurons, and is located within the walls of the GI tract. Although it does receive CNS input through the vagus nerve and spinal cord, it is also able to act independently due to local reflex circuits. 

The gut is not only responsible for digestion but also influences our cognition and mood through its communication with the brain. The vagus nerve plays a vital role in the bidirectional connection between the two systems. Signals from the gut, such as neurotransmitters and information about gut microbiota, are transmitted via the vagus nerve to the brain. In return, the brain also uses the vagus nerve to influence gut function, allowing it to modulate gastrointestinal activities in response to stimuli like psychological stress or anticipation of a meal.

The gut-brain axis not only includes direct neural connections but also indirect connections facilitated through the endocrine and immune systems. The GI tract produces its own hormones that communicate with the brain. For instance, ghrelin, which is produced in the stomach, signals to the brain that it’s time to eat when you are hungry. In turn, the brain initiates hormonal responses that exert influence over gut functions. 

An example of this is the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus, a gland in the brain, senses when our body is under stress and triggers a cascade of events that result in the release of hormones, such as cortisol, by the adrenal glands. Cortisol interacts with various cell types in the gut, including epithelial cells and immune cells, allowing it to regulate transit time, intestinal barrier function, and the composition of the microbiome - the community of microorganisms that reside in the gut. 

Around 70% of our immune system resides in the gastrointestinal tract, specifically in gut-associated lymphoid tissue (GALT). The GALT interacts with the gastrointestinal tract directly, coordinating immune system activity in response to exposure to gastrointestinal contents. In response to exposures like infection or inflammation, immune cells in the gut release signaling molecules called cytokines. These cytokines can enter the bloodstream and even enter the brain, thereby impacting its functions.

The Microbiome: A World Within

The gut microbiome refers to the trillions of microorganisms, including bacteria, fungi, and archaea, that reside within the gastrointestinal tract. Each person has a unique microbiome that is shaped by multiple factors. Genetic and early lifestyle exposures, such as delivery and infant feeding methods, set the foundation. Lifestyle practices, throughout the course of our lives, continue to shape the composition of our microbiome, including diet, medications, alcohol consumption, smoking, physical activity, and sleep patterns. The microbiome has many functions, including: 

Digestion 

The microbiome assists in breaking down complex carbohydrates, fibers, and other food components we cannot digest on our own. This breakdown allows for the absorption of essential nutrients as well as the production of short-chain fatty acids (SCFAs) that play a role in gut health.

Protection From Pathogens

Beneficial gut bacteria can help prevent the growth and colonization of harmful pathogens, thereby protecting against infections.

Synthesis of Vitamins

Some microorganisms in the gut can synthesize essential vitamins, such as vitamin K and certain B vitamins. These vitamins are then absorbed and contribute to various physiological functions in the body.

Immune System Regulation

The gut microbiome plays a crucial role in developing and modulating the immune system. It helps distinguish between harmful pathogens and beneficial microorganisms, preventing unnecessary immune responses and inflammation.

Neurotransmitter Production

Gut bacteria can produce neurotransmitters, including serotonin, dopamine, glutamine, and GABA, which can impact mood and mental health.

Gut Barrier Function 

The microbiome helps maintain the integrity of the gut barrier, preventing potentially harmful substances from entering the bloodstream, where they can trigger inflammation.

Detoxification

Certain gut bacteria are involved in the metabolism of hormones and environmental exposures, like toxins and drugs, aiding in their elimination from the body.

All of these important functions not only play a role in optimizing gut health but also brain function, such that dysbiosis has been associated with disruption to the gut-brain axis. Dysbiosis refers to an imbalance in bacterial composition, activity, or distribution within the gut. This can occur when there is a loss of beneficial bacteria, an overgrowth in potentially pathogenic organisms, a loss of overall diversity, or conditions like small intestinal bacterial overgrowth (SIBO) where colon bacteria have migrated into the small intestine.

Gut Microbiome and Brain Health

While the connection might not be immediately obvious, the microbiome can be at the root of cognitive symptoms such as depression, anxiety, and brain fog. Brain fog is a term used to describe a constellation of symptoms including forgetfulness, difficulty concentrating, dissociation, excessive cognitive effort, difficulty communicating, and fatigue. In dysbiosis, the changes to the microbiome composition result in changes to its metabolic functions, like its ability to produce neurotransmitters and SCFAs, that ultimately impact the gut-brain axis. 

Neurotransmitters play a pivotal role in regulating mood and cognition, and neurotransmitter imbalances have been associated with cognitive impairment, anxiety, depression, memory, and concentration. Certain bacterial strains in the gut produce enzymes that synthesize and metabolize neurotransmitters and their precursors, such as glutamate, GABA, serotonin, dopamine, and tryptophan. Carbohydrate fermentation by gut bacteria also results in the production of short-chain fatty acids. SCFA’s modulate neurotransmitter and neurotrophic factor production in the brain. Neurotrophic factors include nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor (BDNF), which regulate the neurons and microglia, immune cells, in the brain. In psychiatric and neurodegenerative 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. 

Inflammation: The Silent Enemy

The microbiome has an important role in regulating the immune system and barrier functions. Dysbiosis disrupts these processes, leading to systemic and neural inflammation, both of which are fundamental factors at the root of cognitive dysfunction. (13, 43, 68)

Beneficial commensal bacteria in the microbiome regulate immune responses by supporting the development of immune cells called regulatory T cells that prevent unnecessary inflammation. In dysbiosis, immune system activation is triggered, which increases proinflammatory signals. (4)

The microbiome also plays a role in maintaining the integrity of the gut barrier. The gastrointestinal tract is the body’s largest contact point with the outside world. A well-functioning intestinal barrier is crucial for preventing pathogens, toxins, and poorly digested food particles from entering the bloodstream. When this barrier breaks down, in a condition known as intestinal permeability or “leaky gut," it allows for the gastrointestinal contents to enter the bloodstream, triggering the immune system and increasing inflammatory responses. 

Certain beneficial bacteria increase the production of mucus-tight junction proteins, and SCFAs strengthen the intestinal barrier. In dysbiosis, an overabundance of gram-negative bacteria, which contain endotoxins or lipopolysaccharides (LPS), can damage the intestinal lining, leading to intestinal permeability. Some microorganisms also increase the production of a protein called zonulin, which regulates tight junction proteins. Higher levels of zonulin are associated with intestinal permeability. (11) Intestinal permeability is associated with cognitive decline, as well as psychiatric conditions such as anxiety and depression. (55)

SCFAs not only exert a protective influence over the intestinal barrier but also the blood-brain barrier (BBB). The BBB functions similarly to the intestinal barrier, controlling the passage of substances from the bloodstream into the brain tissue. BBB dysfunction or permeability, just like intestinal permeability, is associated with inflammation in the brain and cognitive dysfunction. (38)

Functional Medicine Tests for Gut-Brain Health 

Functional medicine tests are useful tools in identifying the root causes of cognitive changes by evaluating the health of the gut-brain axis. 

Cyrex Intestinal Permeability

The Array 2 by Cyrex Laboratories measures specific biomarkers related to the intestinal barrier, such as antibodies to zonulin and tight junction proteins. This provides information about the integrity of the intestinal barrier and whether intestinal permeability exists.

Organic Acids

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

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.

Nutritional Pathways to a Healthier Gut and Mind 

What we consume not only fuels our bodies and brains but also regulates gut-brain health, influencing the composition and metabolism of the gut microbiota, the integrity of the intestinal lining, and inflammation. As a result, dietary choices can ultimately impact our mood, cognition, and even our susceptibility to neurological and psychiatric conditions. 

Western diets are characterized by high amounts of processed foods, refined carbohydrates, salt, saturated fats, and trans fats, as well as less than desired amounts of fiber, important nutrients, and antioxidants. Some of the prominent foods in the Western diet can stimulate inflammation directly or indirectly through their influence on the microbiome composition. (51) Diets high in sugar have been shown to decrease microbial diversity and increase intestinal permeability, while diets high in plant-based foods and fiber, such as a Mediterranean diet, support the growth of beneficial commensal bacteria that inhibit inflammatory responses. (40)

Food sensitivities, which involve the immune system's reactions to specific food proteins, influence intestinal permeability. They do so by increasing inflammation or stimulating zonulin production. (62) Collaborating with a functional medicine practitioner to either conduct food sensitivity testing or navigate an elimination diet can be helpful in personalizing dietary recommendations to steer clear of potentially harmful foods for your gut.

Prebiotics and probiotics, acquired either through dietary sources or supplements, aid in optimizing the microbiome composition. Prebiotics, non-digestible dietary compounds typically from carbohydrates or fiber, serve as a source of nutrition for beneficial gut bacteria, promoting their growth and activity. These compounds are found naturally in certain foods like fruits, vegetables, whole grains, and legumes or can also be taken in supplemental form. Common prebiotic supplements available include inulin, fructooligosaccharides, resistant starch, and galactooligosaccharides. Probiotics are living beneficial microorganisms, usually yeast or bacteria, that are found in fermented foods, such as yogurt, sauerkraut, and kimchi. Incorporating more fermented foods into your diet or using oral probiotic supplements have both been found to improve microbial composition and reduce inflammation.

Lifestyle Choices that Promote Gut and Brain Health

The gut-brain axis is shaped not only by our dietary choices but also by the lifestyle practices we engage in. Physical activity, stress management, and sleep all have a profound impact on both the gut and the brain, thereby influencing the intricate relationship between the two.

Physical Activity

Exercise habits influence the microbiome and gut inflammation. Over-exercising has a negative impact on the composition of the microbiome and increases intestinal permeability. On the other hand, regular, lower-intensity exercise exerts protective effects, improving the microbiome composition and increasing SCFA production.

Exercise also directly influences brain health and neuroplasticity by stimulating the release of neurotrophic factors like BDNF, increasing blood flow, and improving glucose and lipid metabolism, which aids in delivering necessary fuel to the brain. Studies show it helps to improve cognitive functions, such as memory and attention, and also helps to prevent cognitive decline.

Stress Management

Stress negatively impacts the gut-brain axis through its effects on the nervous, endocrine, and immune systems. Under stress, the brain uses the autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis to send signals to the gut. Research shows that stress changes intestinal permeability, intestinal motility, intestinal secretions, microbiome composition, and intestinal inflammation. (29) Psychological stress is also associated with decreased cognitive functioning, cognitive decline, depression, and anxiety.  

Mind-body therapies stimulate the body’s relaxation response to counteract the negative neuroendocrine effects of stress. Some of these techniques include mindfulness, meditation, yoga, deep breathing, progressive muscle relaxation, and biofeedback. Mindfulness practices, for example, have been used to improve cognitive function, treat gastrointestinal symptoms, and improve mood.

Sleep

Sleep plays a vital role in supporting cognitive health through memory consolation, hormone balance, and detoxifying the brain. Sleep disruption changes microbiome composition as well as increasing inflammatory cytokines. These underlying mechanisms contribute to its association with decreased cognitive ability, depression, and anxiety. 

Good sleep hygiene practices to implement to improve sleep quality include sticking to a consistent sleep schedule, getting exposure to natural light during the day, ensuring the room you sleep in is cool, dark, and quiet, limiting screen exposure in the evenings, and avoiding heavy meals and caffeine too close to bedtime. 

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Why The Gut is The Second Brain: Key Takeaways 

Recognizing the critical role of the gut-brain axis in cognitive health is essential. Microbiome composition and activity, intestinal permeability, and inflammation all significantly disrupt this axis. Functional medicine tests are invaluable in gaining insight into the function of the gut-brain axis, guiding individuals towards tailored diet and lifestyle choices. By embracing the gut-brain connection and proactively nurturing this connection, individuals are empowered to enhance their overall well-being.