The human body consists of multiple organ systems that work together to support vital bodily functions. Each of our body systems is interconnected and dependent on each other. For example, the heart (circulatory system) does not beat unless our brain (nervous system) sends signals telling it to. When one system is affected, it can have far-reaching consequences on the entire body.
The gut, endocrine system, and immune system are in constant communication with each other through hormonal messengers, nerves, and microbial metabolites. Understanding and fostering the synergy between these systems is extremely important as chronic, inflammatory health conditions are on the rise, including autoimmune disease, metabolic syndrome, obesity, and cancer. Effective management of these conditions may involve exploring the relationship between these systems and considering interventions that support overall health and well-being.
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Overview of the Three Key Players
Before discussing how they are all connected, let's get started by reviewing the endocrine, gastrointestinal, and immune systems:
What is the Endocrine System?
The endocrine system, also known as our hormonal system, consists of several glands that produce and secrete hormones, which serve as the body’s messengers. They travel through the bloodstream, where they communicate with other tissues and organs to regulate biological functions such as metabolism, digestion, growth and development, mood, sexual function, sleep, and blood pressure.
What is the Gastrointestinal System & What is the Microbiome?
The gastrointestinal system consists of a series of organs connected to one another, from mouth to anus, responsible for the digestion of food and absorption of important nutrients. It is also home to trillions of microorganisms, known as the microbiome. These microorganisms have a variety of functions, including breaking down food compounds, synthesizing certain vitamins and amino acids, and interacting with our immune system. Each person’s microbiome is unique and can change based on lifestyle factors, including diet, stress, and environmental exposures. Imbalances in the microbiome are associated with a variety of health issues, including gastrointestinal conditions like irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), metabolic syndrome, cardiovascular disease, depression, anxiety, skin conditions like psoriasis and eczema, and immune system dysregulation making individuals more susceptible to conditions like autoimmune diseases and allergies.
What is the Immune System?
The immune system is a network of organs and cells that recognizes and protects against foreign invaders to help maintain health. The skin and mucous membranes serve as physical barriers and first-line defenders of the immune system. The bone marrow, thymus, and spleen are involved in white blood cell formation and storage. The white blood cells are responsible for searching for and responding to pathogens. The lymph nodes, tonsils, and adenoids help to trap foreign invaders. The gut secretes enzymes and contains the microbiome that supports a healthy balance of microorganisms.
How Do Hormones Influence Gut Health and the Immune System?
Hormones influence gut health through a variety of mechanisms, including regulating motility, intestinal permeability, and the composition of the microbiome. Gastrointestinal motility refers to the movement of food through the gut to absorb nutrients and water while eliminating waste. This is accomplished by coordinated contractions and relaxations in the smooth muscles of the gastrointestinal tract, which are controlled by nerves, hormones, and immune system mediators. Ghrelin is a hormone secreted primarily by the stomach and small intestine that increases motility and gastric emptying.
Thyroid hormones also play a role in regulating motility, as demonstrated in the case of hypothyroid patients showing delayed transit times and reductions in motor activity in the stomach, small intestine, and colon. The gastrointestinal lining should be a semipermeable barrier, only allowing for the absorption of fully digested nutrients and water. Intestinal permeability, also known as leaky gut, occurs when this barrier gets disrupted, allowing larger molecules such as pathogens, toxins, and poorly digested food proteins to be absorbed. Certain hormones, like cortisol released during stress, can contribute to the breakdown of the gastrointestinal lining. In addition to inducing intestinal permeability, cortisol can disrupt the composition and overall diversity of the microbiome. Changes in sex hormones, like estrogen and progesterone, during pregnancy and menopause also influence the composition of the microbiome.
Hormones communicate with the immune system, helping to coordinate immune responses and maintain equilibrium within the immune system. When hormone levels become disrupted, several aspects of the immune system can be affected, increasing susceptibility to conditions such as autoimmune diseases and infections. Women are at a higher risk of developing autoimmune diseases than men. In part, this is likely due to sex hormones’ effects on immunity. Estrogen turns on genes for cytokines that coordinate immune responses against pathogens and can also exacerbate autoimmune responses. Furthermore, it activates B cells, a type of white blood cell that makes antibodies. Antibodies are proteins that mark and attack foreign substances and pathogens. In autoimmune diseases, B cells make autoantibodies against the body’s own tissues. Androgens, like testosterone, are largely immunosuppressive and can decrease the activity of immune cells involved in autoimmune reactions. Cortisol influences the activity of immune cells like B cells and T cells. Chronic, stress-induced elevations in cortisol suppress their activity and responsiveness, increasing susceptibility to infections.
How Does Gut Health Affect Hormonal and Immune Balance?
The gut influences both hormone production as well as metabolism. The lining of the gastrointestinal tract contains cells called enteroendocrine cells that release their own hormones. For example, when you eat, these cells release hormones like cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) that regulate digestion and blood sugar. The gut also communicates with the brain to influence hormone production and regulation outside of the gastrointestinal tract. The gut microbiota produce neurotransmitters, like serotonin, that influence hormone production in the brain and short-chain fatty acids (SCFAs) that regulate hormone function, like improving insulin sensitivity.
Hormones are metabolized in the liver and then excreted into the bile for elimination through the stool. Certain strains of gut bacteria make an enzyme, beta-glucuronidase, that deconjugates these estrogen metabolites, allowing them to re-enter circulation and affect overall hormone balance.
Between 70-80% of our immune cells are present in the gut, where they interact with the microbiome, influencing the development and activity of our immune system and protecting against infections. Commensal bacteria prevent pathogen colonization through nutrient and resource competition, maintaining proper pH levels in the GI tract, biofilm production, producing antimicrobial substances, stimulating secretory immunoglobulin A (IgA) production, and maintaining a healthy mucus layer.
Some microorganisms support the development of immune cells, known as regulatory T cells, that help to balance immune responses, while others can promote the activity of immune cells involved in inflammation. Alterations of the microbiome (dysbiosis) have been observed in autoimmune diseases. Under normal circumstances, the gastrointestinal lining would prevent pathogens and toxins from entering the bloodstream. When intestinal permeability is present, they are able to be absorbed and interact with the immune system, triggering inflammatory responses and increasing the risk of allergies and autoimmune diseases.
How Does the Immune System Affect Hormones and Gut Health?
As previously discussed, chronic stress and its associated hormonal responses have a profound impact on immune function. It's important to note that this connection operates as a bidirectional relationship. Immune cells release signaling molecules called cytokines in response to infection or inflammation. These cytokines affect the function of the hypothalamus-pituitary-adrenal (HPA) axis and stimulate the release of stress hormones like cortisol. These inflammatory cytokines can also affect the hypothalamus-pituitary-gonadal (HPG) axis and the production of hormones like gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) involved in fertility and reproduction. Inflammation can directly impact ovarian function and hormone production, as seen in the case of polycystic ovarian syndrome (PCOS), where chronic inflammation is linked to excess androgen production.
The immune system in the gut, called the gut-associated lymphoid tissue (GALT), is responsible for identifying and removing pathogens. The GALT is in constant contact with the commensal microorganisms in the gut and must maintain immune tolerance toward them, requiring properly functioning regulatory T cells. Dysregulated GALT function is associated with gastrointestinal conditions like inflammatory bowel disease. Increased immune system activity and inflammation, such as during active infections, impact gastrointestinal motility, most likely through smooth muscle contractility. Systemic autoimmune diseases can also cause gastrointestinal issues through mechanisms like immune complex deposition and chronic exposure to inflammatory cytokines.
How Can Lab Testing Be Used to Evaluate Hormones, Gut Health, and The Immune System?
Functional medicine labs provide an opportunity to explore the complex interactions between the gut, hormones, and immune system that might otherwise be missed. By ordering these labs in tandem, rather than analyzing these systems in isolation, practitioners can identify the root causes of patients’ dysfunction and personalize holistic treatment plans accordingly.
Gut Health Tests
The GI Effects test by Genova Diagnostics provides insight into microbiome composition, gastrointestinal inflammation, and digestive capacity. Using both culture and polymerase chain reaction (PCR) analysis, the test can reveal the relative amounts of important commensal bacteria as well as identify any potential pathogens like bacteria, fungi, and parasites. Elevations in markers like calprotectin, a protein produced by neutrophils, and eosinophil protein X (EPX) can indicate increased immune system activity in the gut.
Cyrex’s Array 2, also known as the Intestinal Antigenic Permeability Screen, measures antibodies against specific proteins associated with the gut lining to assess intestinal permeability.
Hormone Panels
There are various testing methods available to measure hormones, including blood, saliva, and urine. Although blood tests are the traditional choice for identifying endocrine conditions, there are also advantages to saliva and urine tests. They provide non-invasive alternatives for patients desiring a more comfortable collection experience and can also reveal additional information about free or bioavailable hormone levels and hormone metabolism.
The DUTCH Complete is a dried urine test that not only measures cortisol, DHEA, estrogen, progesterone, and testosterone but also their metabolites. Like the salivary hormone profile, it measures cortisol levels at multiple points throughout the day to uncover any deviations from the normal circadian rhythm. It also includes melatonin, a hormone involved in regulating our sleep-wake cycle, that is not included in the other testing options mentioned.
Immune System Function Tests
The assessment of immune markers in lab testing can identify immune system dysfunction like a weakened immune system, inflammation, and autoimmunity.
A complete blood count with differential (CBC w/ diff) measures the total amount of white blood cells as well as the breakdown of the various types of white blood cells including neutrophils, lymphocytes, eosinophils, monocytes, and basophils. Changes in these markers provide information about what type of immune responses might be occurring. For example, low white blood cells can indicate a weakened immune system or immune system suppression, elevated eosinophils can occur in allergies or parasitic infections, and elevated neutrophils are often seen in bacterial infections.
Immunoglobulins are proteins secreted by immune cells to identify and neutralize foreign substances and pathogens. The Immunoglobulins Panel by Access Medical Laboratories measures the total amount of various immunoglobulins (IgA, IgG, and IgM), reporting whether the immune system is struggling to produce enough immunoglobulins, as seen in immune deficiency states, or producing too many, as seen in chronic inflammatory conditions.
Exposure to chronic infections can impact the body’s immune responses, potentially depleting the immune system, promoting inflammation, and/or triggering autoimmunity. (6, 7, 65).
Antinuclear antibodies (ANA) are a type of autoantibody commonly seen in autoimmune disease. If ANA is positive, an extractable nuclear antigen (ENA) test can be ordered to help identify more specifically which autoimmune disease is present.
C-reactive protein (CRP) is a protein released from the liver in the presence of inflammation. Sedimentation rate (ESR) measures the rate at which red blood cells settle at the bottom of the collection test tube. If inflammation is present, the red blood cells tend to clump together and settle more quickly, causing a higher ESR. Both of these markers tend to be elevated in autoimmune diseases.
Holistic Interventions for Balanced Interconnectivity
Holistic treatment plans for the gut-hormone-immune axis include multi-faceted and personalized interventions designed with the relationship of these essential body systems in mind to optimize interconnected health.
Nutrition for Balanced Gut Health, Hormones, and Immune Systems
A whole-foods, nutrient-dense, and high-fiber diet can support optimal hormone balance, gastrointestinal function, and immunity. (19, 47, 66)
An example of such a diet would be the Mediterranean diet, which emphasizes fruits, vegetables, legumes, whole grains, and healthy fats and restricts processed meats, foods, sugars, and oils. High-fiber plant foods help to support beneficial microbiome diversity in the gastrointestinal tract. Vitamins, minerals, and phytonutrients found in fruits and vegetables help support hormone production and metabolism as well as immune system function (8, 54). Removing inflammatory foods like processed sugars and trans fats helps to prevent both gastrointestinal and systemic inflammation that can disrupt the gut-hormone-immune axis. (11)
Lifestyle Adjustments for a Healthy Gut, Hormones, and Immune System
Sleep deprivation is associated with changes to immune system function, changes to microbiome composition, and hormone imbalances. The National Sleep Foundation recommends 7-9 hours of sleep for adults. Some good sleep hygiene practices to implement to improve sleep quality include: stick to a consistent sleep schedule, get daytime natural light exposure, make sure the bedroom is cool, dark and quiet, limit screen exposure in the evenings, and avoid heavy meals and caffeine too close to bedtime.
Stress management techniques, like meditation and breathing exercises, help to regulate the HPA axis and cortisol levels. Stress management techniques have been used to improve symptoms in gastrointestinal conditions, reduce inflammatory cytokines, and balance hormones besides just cortisol, including DHEA, melatonin, and testosterone.
Adding an exercise routine into your weekly schedule can help to balance the gut-hormone-immune axis. Regular physical activity enhances the amounts of beneficial microorganisms in the microbiome, improves sleep quality, reduces inflammation, strengthens the immune system, and regulates hormone production and function. (23, 50)
Herbs & Supplements for a Healthy Gut, Hormones, and Immune System
Probiotics and Ashwagandha are options that may support a healthy gut, help maintain balanced hormones, and support a healthy immune system.
Probiotics
Probiotics are supplements that contain live microorganisms like healthy bacteria and yeast. Probiotics may support gut and immune function by promoting microbiome diversity, enhancing intestinal barrier function, and helping to maintain a healthy balance of microorganisms in the GI tract. They also interact with immune cells in the gastrointestinal tract to modulate immune cell activity. Probiotics are also being explored for their potential in supporting hormonal balance, such as in PCOS, insulin resistance, and stress-related cortisol imbalances.
Ashwagandha
Ashwagandha, or Withania Somnifera, is an herbal adaptogen. Adaptogens may help the body adapt to stress and maintain homeostasis. Ashwagandha has been used to help manage stress, support balanced cortisol levels, and promote a healthy immune system. These mechanisms of action can help to support the gut-hormone-immune axis.
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Summary
The interdependence between the body’s systems is particularly evident in the complex relationship between the gastrointestinal, endocrine, and immune systems. Dysregulation in gut health, hormones, or immunity (or all three) can increase the susceptibility to various health challenges. As we continue to deal with increasing prevalence of chronic health conditions, it becomes increasingly evident that the key to successful management lies in considering and investigating the interconnectedness of these body systems to create personalized and holistic approaches.
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