The Gut-Brain Connection: Who Cares?

Who should care about the Gut-Brain Connection? Anyone who has, or cares about someone with, a chronic health concern.

Six in ten Americans live with at least one chronic health concern, such as pain, arthritis, depression, anxiety, heart disease and stroke, cancer, diabetes, and many others.  Chronic illnesses are the leading cause of death and disability in America, and they are also a leading driver of health care costs. (0) According to the Centers for Disease Control, of the $3.5 Trillion spent on health care annually in the U.S., 90% is spent on the management of chronic illness.  Statistics are staggering and highlight the need for a new approach.

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Some examples include:

  • 1 in 5 U.S. adults experience mental illness each year (> 65 million)

  • 50 million Americans suffer from chronic pain

  • Over 16 million Americans live with an Autoimmune Disease

  • 1 in 6 U.S. youth aged 6-17 experience a mental health disorder each year

  • 5.8 million Americans are living with Alzheimer’s Disease

  • Every year over 1.7 million are diagnosed with cancer

  • Every year about 805,000 Americans have a heart attack

  • 1 in 25 is diagnosed with serious mental illness (>13 million)

  • 50% of all lifetime mental illness begins by age 14, and 75% by age 24.

  • Suicide is the second leading cause of death among people aged 10-34.

(18-23)

Considering the fact that the number of prescriptions being written each year for conditions such as diabetes, high cholesterol, depression, and anxiety, one would think that these ailments would be fading away. However, chronic mental and physical illnesses not only dominate our culture today; they are on the rise. Though American’s comprise only 5% of the world’s population, we consume 50% of its pharmaceutical drug supply. (24) Not so coincidentally, prescription drugs have emerged as the third leading cause of death in the U.S., just after heart disease and cancer. Around half of those who die take their medications correctly; the other half die because of errors, such as taking too high of a dose or using a medication despite clear contraindications. (25)

However, a closer look reveals that these medications aren’t intended to cure illness, but merely manage symptoms, while the underlying cause of the condition goes untreated.  As the embers of chronic illnesses continue to smolder within the body, a once local problem can spread to multiple regions through the insidious effects of chronic inflammation.  The resulting health concerns are often viewed as unrelated and isolated entities, while their cause is never identified or addressed. In this article, we will uncover a common thread that connects some common physical and mental health conditions and explore a new paradigm emerging that addresses these conditions at their root.

THE HIDDEN CAUSE

Since the industrial revolution, the world in which we live has changed more drastically than any other time in human history. This change has led to a rapidly evolving mismatch between our biology and our environment. In an analogy comparing the environment to computer software and our genetics to computer hardware, we could say that that the two are no longer compatible. Because of this, many error messages (symptoms/diseases) are manifesting in our 21st Century lives. A key common thread connecting these error messages is chronic low-grade inflammation.

Researchers now believe that inflammation is the fuel that drives most all chronic illnesses, including cardiovascular, neurodegenerative and autoimmune disease, along with arthritis, stroke, diabetes, and cancer.  It is no surprise that mental health problems are also now understood to be the result of inflammation’s effect on the brain. Thanks to new technology and the growing field of psychoneuroimmunology, we are beginning to understand the complex interconnections between our immune system, inflammation, and mental health.

To have a better grasp on the future of medicine, we must go back to the past. Almost 2,500 years ago, Hippocrates stated, “All disease begins in the gut.” We are just now beginning to understand what that means. In recent years, researchers have focused on how the integrity of the intestinal lining and types of microbes that live in our gut impact overall health.  It is now understood that much of the fuel driving chronic diseases originates from these very tissues. Having a basic understanding of these new insights can help us overcome many of the current chronic illnesses we face today and prevent the onset of new ones.  The best way to begin understanding this is through basic anatomy.

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THE GI SYSTEM

The human gastrointestinal system has three primary purposes. The first purpose is to break down and absorb nutrients. Although the small intestine is only 18 feet long, its impressive architecture with fingerlike projections significantly increases its surface area for maximal nutrient absorption. If stretched out, the surface area of the small intestine would reach the size of a double’s tennis court. That means our gut has over 100 times as much contact with the environment as our skin.  Although essential for proper nutrient absorption, this significant amount of exposure to the “outside world” is also the reason the gut contains 70-80% of the immune cells in our body, making the GI tract the largest immune organ. (7)

Functioning as that protective barrier, keeping unwanted foreign substances in our bowels from entering into our bloodstream, is the GI system’s second purpose. Though you may have never considered it, the contents of our intestines are ‘outside’ of our bodies. This fact is vital since the intestines contain such things as food particles, enzymes, toxins, bacteria, and bacterial waste products.  The gut barrier must remain protective and selective for us to be healthy, happy, and strong.

The third purpose of the human gastrointestinal system is to provide a hospitable environment for the trillions of microorganisms that live there.  The diverse ecosystem that resides within us is referred to as the microbiome. We now know that our gut contains over 100 trillion microorganisms from over 1000 different species, while only about 1 trillion cells make up the human body. This means that 99% of the cells that we carry around with us each day and think of as ‘self’ are actually foreign microbes. The 23,000 genes that make up the human blueprint pale in comparison to the approximately 2 million different genes contained within our tiny companions.  Not only are these statistics interesting, they are evidence that the microbiome has a profound effect on our lives, in everything from determining our mood, to what foods we are craving, to balancing our hormones, to regulating our immune system.

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THE MICROBIOME

Researchers continue to discover new ways in which this symbiotic relationship impacts our health and well-being.  For example, we now know that the microbiome has a profound structural effect on our gut.  “Good” bacteria will help to stimulate the growth of the cells that line our GI tract, while “bad” bacteria will create toxins that cause a breakdown of the gut wall through inflammation. The resulting porous gut barrier allows for the passage of antigens and toxins that negatively impact our health in many ways.

FUNCTIONS OF THE MICROBIOME INCLUDE:

  • Regulate metabolism

  • Promote normal GI function

  • Protect us against harmful bacteria, viruses, and parasites

  • Regulate immune function

  • Break down dangerous chemicals

  • Synthesize vitamins

  • Convert nondigestible carbohydrates into forms that can be used for energy

  • Help maintain the health of the gut lining

  • Help us absorb minerals

  • Decrease inflammation

  • Produce and metabolize neurotransmitters

  • Expression of neurotransmitters

  • Influence Blood-Brain Barrier (BBB) and Gut Blood Barrier permeability

THE GUT-BRAIN AXIS

Proper functioning of the gut is so important, it has its own nervous system. The name given to this incredible neural network is the enteric nervous system (ENS), which develops from the same embryologic tissue as the central nervous system (CNS). The ENS is so powerful in its influence over our health that it has affectionately been nicknamed “The Second Brain.”

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Neurologically, the two systems communicate via a large nerve in the brain stem called the Vagus nerve. Information is continuously moving from the gut to the brain and from the brain to the gut. However, this superhighway does not have an equal number of lanes moving in both directions. Surprisingly, 90% of the communications are traveling Northward, from the gut to the brain.  Research has also recently shed much light on this bi-directional communication that exists between the gut and the brain.

There is a significant amount of communication through bloodborne pathways involving hormones, neurotransmitters, metabolic cofactors, and other signaling molecules. The neural pathways are more rapid and more specifically targeted, while the bloodborne channels are slower and more generally targeted.  Scientific advances have led to a greater understanding of the ongoing bidirectional “crosstalk” between the digestive system and the brain, which has been named the Gut-Brain Axis.

The physiologic linking of emotional and cognitive brain centers with gastrointestinal function can have a profound influence on our health. (1)  For example, changes in microbiome diversity (Dysbiosis) can strongly influence the production and secretion of the neurotransmitters serotonin, GABA, norepinephrine, and dopamine. (12)  In fact, 90% of the serotonin in our body is produced in our gut, by gut bacteria.  Dopamine is considered the primary regulator of cognitive functions such as decision-making, attention, memory, motivation, and reward.  A significant portion of its production also comes from the gut. Evidence points to alterations in the microbiota-Gut-Brain Axis as being a critical component of several neuropsychiatric disorders involving compromised dopamine transmission. (12)

Dysbiosis is the term given when an individual has an unhealthy imbalance of the organisms present in their gut microbiome. We, as a species, have developed alongside our little friends over tens of thousands of generations.  The profound synergy that exists between us as the host, and the trillions of microbes that reside on our body’s surfaces, is only beginning to be understood. With that comes the understanding of what can happen when that delicate balance is breached.

OUR PROTECTIVE BARRIERS

The barrier between our intestinal contents and the inside of our bodies is called the Gut Blood Barrier (GBB).  This barrier is composed of only a single layer of cells interconnected by protein junctions, referred to as “tight junctions,” for enhanced absorption.  In different regions along the length of the GI tract, the type of cells within that layer change, each having specific barrier functions. (4)  Food particles, vitamins, and minerals should be absorbed through the intestinal cells, but can also enter through the junctions if those junctions become compromised. (7)  Intestinal absorption must remain very selective because whatever passes through that barrier, enters directly into the bloodstream. This is why the gut-associated lymphoid tissue (GALT), the vast majority of the immune cells in our body, resides just beneath the intestinal lining, waiting to intercept any unwanted intruders.

WHAT THE GUT AND BRAIN SHARE IN COMMON

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Just as the GBB permits the passage of nutrients and protects against toxins entering the body, the Blood-Brain Barrier (BBB) allows the passage of nutrients and protects against toxins entering the brain. It is only in the past five years that researchers identified that the brain contained its own lymphatic system, with the primary purpose of connecting it to the immune system.  Since the GBB and the BBB share common structures and mechanics, environmental factors that can damage the integrity of the GBB can also damage the integrity of the BBB.   Research has also shown that gut bacteria can influence both the GBB and the BBB through hormonal secretion, metabolic cofactors, or other inflammatory mechanisms.  These connections help to explain what has been called the “Leaky Gut – Leaky Brain” phenomenon. (4)   It is no wonder that in recent literature, there is growing evidence that increased intestinal permeability and the inflammation that follows is not only detrimental to our physical health, but it also plays a significant role in the development of many psychiatric disorders, including depression and anxiety. (7)

LEAKY GUT

Our digestive system, by design, must be permeable.  However, when intestinal permeability becomes increased inappropriately, allowing unwanted particles to pass through it into our bloodstream, we refer to it a Leaky Gut Syndrome. As previously stated, this is very serious and can cause widespread damage. Searching for the underlying cause of a health condition can be challenging. It is especially challenging when Leaky Gut Syndrome is present, because contrary to popular belief, many individuals with this condition and it’s unfortunate sequelae, have no GI symptoms at all. Most often, some environmental trigger, or combination of triggers over time, lead to damage of the intestinal barrier, causing increased permeability.

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The underlying causes of Leaky Gut are many and include factors from our external and internal environments. Examples include, but are not limited to:

  • Stress – Stress significantly changes our physiology and is often a driver of chronic inflammation.

  • Lifestyle – This includes things such as quality of sleep, quality of air, exercise, and recreation.

  • Poor Diet – Diets containing sugar, wheat, artificial sweeteners, processed foods.

  • Food Additives – Found in most all processed foods.

  • Medications – Prescription and OTC

  • Infections – Chronic gut infections can go on undiscovered for years.

  • Heavy Metals – Some individuals have difficulty ridding their bodies from heavy metals. This can lead to a buildup of damaging toxic chemicals.

  • Xenobiotics – Common environmental chemicals that we are exposed to, that are not natural to our bodies. These chemicals can interact with and change our physiology.

  • Dysbiosis – An unhealthy imbalance of gut microbes that is common in our society.

  • Chronic Inflammation – From a variety of sources

  • Gut-Brain Dysfunction – As discussed

  • Oxidative Stress – Stress on the body that is caused by the cumulative damage of free radicals.

  • Genetics – Individuals have their own unique predispositions to certain illnesses.

This permeability allows bacteria and other antigens direct access to our bloodstream.  One specific example is how a leaky gut allows for the translocation of lipopolysaccharides (LPS), molecules found on the outer membrane of certain bacteria, from the gut into the circulation. LPS is so dangerous and damaging to our health, scientists have given it another, more descriptive name: Endotoxin.

LEAKY GUT, PSYCHIATRIC CONDITIONS, AND AUTOIMMUNITY

LPS activates our immune system, leading to low-grade systemic inflammation, a major player in all forms of chronic illness.  (1)  This fact is evident in psychiatric conditions where anxiety and depressive disorders manifest as a result of lipopolysaccharides (LPS) passing through a compromised gut barrier, resulting in low-grade systemic inflammation. (3) Numerous studies support that a leaky gut may be the underlying cause of increased BBB permeability triggered by inflammation. (4)  Other lifestyle factors also link inflammation and mental health conditions, including a poor diet, physical inactivity, insulin resistance, oxidative stress, and mitochondrial dysfunction. (2)

To further complicate the matter, this immune activation may mistakenly attack some of our own body’s tissues creating an autoimmune condition. The tissues that will be affected are a consequence of genetic susceptibility. Dr. Alessio Fasano, a Harvard researcher, considered the world’s leading expert in Leaky Gut Syndrome, believes that increased intestinal permeability is a central causative factor in all autoimmune diseases. It is understood today that various autoimmune disorders are also known risk factors of mental illnesses such as major depression, schizophrenia, and psychotic disorders. It is also believed that autoantibodies could play a significant role in the development of depression and that autoimmune and depressive disorders may originate from a common source. (7)

Similarly, the microbial changes that negatively impact the gut barrier integrity in obesity and Type 2 Diabetes are linked to a Blood-Brain Barrier (BBB) compromise seen in Major Depressive Disorder (MDD). As with other physical conditions, the relationship between diabetes, obesity, and increased risk for mental health problems is bidirectional. Not only is the prevalence of depression elevated in patients with Type 2 Diabetes, but depressed patients are also more prone to develop diabetes later in life. The enhanced risk of developing depression is not just confined to patients with diagnosed diabetes but also extends to patients with undiagnosed and prediabetes, a total of approximately 115 million Americans. (11)

INFLAMMATION

Numerous studies have investigated the immune and or inflammatory status of patients with MDD, schizophrenia, bipolar disorder, and autism. One of the most consistent findings has been the observation of high levels of inflammatory blood markers, notably C-reactive protein, Interleukin-6, TNF Alpha, and Interleukin-1.  Results go on to further characterize a specific inflammatory profile associated with MDD. (9,1) The source of this inflammation, at least in part, is well known; immune activation and associated inflammation related to gut-derived bacterial LPS or various food antigens. (7)  Leaky gut with resultant immune activation has also been correlated with suicidal behavior, where patient’s inflammatory markers upon arrival were predictive of the length of inpatient care. (1)

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As our knowledge of the immune system’s role in these health conditions continues to grow, the importance of measuring appropriate inflammatory markers in patients with psychiatric illnesses like depression and anxiety becomes ever more evident. In clinical practice, inflammation provides a guide to various modalities for symptom management by indicating potential responsiveness to specific therapeutic strategies. (8) Thus when inflammation and depression co-occur, treating them in tandem may enhance recovery and reduce the risk of recurrence. The bidirectional link among depression, inflammation, and disease suggest that effective depression treatments could have a far-reaching impact on mood, inflammation, and overall health. (8)

Although we know that chronic inflammation leads to many severe health conditions, the inflammation itself is not the underlying cause.  Discovering that root cause is not often a simple task but requires careful investigation of a patient’s personal and family medical history, psychosocial history, physical, and laboratory evaluation.  More often than not, the underlying cause is multi-factorial, involving such things as inappropriate exercise, inadequate sleep, infection, stress, or the residual effects of previous trauma.  In the case of clinical depression, the cause is also clearly bi-directional.

Studies evaluating clinical depression and inflammatory markers including C reactive protein (CRP), IL-1 and IL-6 supported three separate causal pathways; one where the depression caused the inflammation and resulting physiologic changes, one where the inflammation from another source caused depression, and one where both psychological and physical issues created a destructive, vicious cycle. (10)  Likewise, depression, childhood adversity, stressors, and diet can all influence the gut microbiome and promote intestinal permeability, another pathway to signal inflammatory responses. (8)  It is also well accepted today that stress by itself can induce gastrointestinal dysfunction leading to physical, immunological, and endocrine changes that predispose the patient to more significant psychiatric illness. (15)

A CHANGING PARADIGM

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A shift is occurring in the way we approach chronic illnesses of all types. More attention is being placed on prevention and addressing the underlying cause of disease, rather than just treating symptoms. Recent scientific literature demonstrates that chronic illnesses develop through the complex interaction between our genes and the environment, with environmental factors being the root cause up to 90% of the time. Functional/Integrative Medicine has developed through this movement and is growing exponentially both in clinical research and in practice. This method looks past the diagnosis of disease, to seek out the underlying cause of chronic illness through an investigative approach.  The physician/drug centered paradigm to care is waning as a new, evidence-based, patient-centered, team-approach to care evolves.

This new model includes research and treatment of mental health conditions. The scientific literature has debunked the serotonin model of depression and has replaced it with the concept of psychoneuroimmunology. (16, 17) No longer is the ‘one source-one drug’ approach to care acceptable.  The new holistic model explores the ongoing bi-directional communication between the gut, the immune system, and the brain. The microbiome is now viewed as a newly discovered organ, with profound and far-reaching effects on our mental and physical well-being.

Given our new awareness about the complex interconnections that underly our chronic health concerns, we must insist on adopting integrated treatment strategies to treat conditions like depression, anxiety, bipolar disorder, and obsessive-compulsive disorder. Plans should be personalized to an individual’s specific needs and may include such things as psychotherapy; counseling; stress management techniques; exercise prescriptions; dietary changes; detoxification protocols; antimicrobials; pre- and probiotics. Analytical, cognitive, and behavioral therapies can support the patient emotionally, while addressing biological imbalances supports them physically. While all of these treatments are effective in their own right, it is the synergistic effect of an integrated approach that guides the healthcare revolution into the 21st century.

REFERENCES:

(0) https://www.cdc.gov/chronicdisease/index.htm

(1) https://www.ncbi.nlm.nih.gov/pubmed/30347427

(2) https://www.ncbi.nlm.nih.gov/pubmed/?term=Intestinal+dysbiosis%2C+gut+hyperpermeability+and+bacterial+translocation%3A+missing+links+between+depression%2C+obesity%2C+and+type+2+diabetes

(3) https://www.ncbi.nlm.nih.gov/pubmed/?term=Increased+human+intestinal+barrier+permeability+plasma+biomarkers+zonulin+and+FABP2+correlated+with+plasma+LPS

(4) https://www.ncbi.nlm.nih.gov/pubmed/30340384

(5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604320/

(6) https://www.researchgate.net/publication/266325749_The_role_of_IgG_hypersensitivity_in_the_pathogenesis_and_therapy_of_depressive_disorders

(7) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987016/

(8) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511978/

(9) https://www.ncbi.nlm.nih.gov/pubmed/28122130

(10) https://www.ncbi.nlm.nih.gov/pubmed/19188531

(11) https://www.ncbi.nlm.nih.gov/pubmed/30513310

(12) https://www.ncbi.nlm.nih.gov/pubmed/31098656

(13) https://www.ncbi.nlm.nih.gov/pubmed/28888668

(14) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859957/

(15) https://www.ncbi.nlm.nih.gov/pubmed/29016169

(16) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238082/

(17) https://www.researchgate.net/publication/260371138_Immunology_of_Major_Depression

(18) https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHNationalFindingsReport2018/NSDUHNationalFindingsReport2018.pdf

(19) https://www.ncbi.nlm.nih.gov/pubmed/30742204

(20) https://www.ncbi.nlm.nih.gov/pubmed/15939837

(21) https://www.nimh.nih.gov/health/statistics/suicide.shtml

(22) https://www.cdc.gov/media/releases/2017/p0718-diabetes-report.html

(23) https://www.cdc.gov/mmwr/volumes/67/wr/mm6736a2.htm

(24) https://naturalsociety.com/composing-5-percent-world-population-americans-take-50-percent-pharmaceutical-drugs/

(25) https://www.ncbi.nlm.nih.gov/pubmed/25355584