THE ROLE OF THE GI TRACT IN IMMUNE FUNCTION 101 “If your name’s not down, you’re not coming in”

In this weeks article I wanted to delve into the science behind some of the systems-biology in Functional Medicine (FM), and talk about the integrative relationship between the digestive tract & the immune system.

By design, the gastrointestinal tract (GI) is designed to break down and absorb large amounts of nutrients in a relatively short space of time. To accomplish this, the architectural feature of folds and fingers, called villi (which I have written about several times in some of my previous articles) which greatly expands the surface area of the GI tract, especially the small intestines, where the 80-90% of nutrient absorption occurs. However, despite this expansive surface area, about the equivalent size of a tennis court in surface area, is only one cell-layer thin, and therefore represents a highly vulnerable interface with the antigen-rich external environment of the gut lumen. The lumen is the biological abyss or empty space within the hollow tubular structure of the intestinal tract which is technically classed as “outside of the body”. This vulnerability requires a highly coordinated cooperation between GI cells and the immune system. In fact, as the evidence suggests, 70-80% of our immune cells reside in the GI tract.

The foundations of FM is made up of a number of core philosophies & principles that collectively make the ‘systems-biology’ approach to health, or ‘functional wellness’ as I like to call it. FM utilises cutting edge evidence-based testing methods to comprehensively assess dysfunctional patterns, imbalances, deficiencies & physiological damage within the core of systems-biology. An experienced FM clinician carries out critical analysis of the laboratory data & the relationships between what the data is showing in order to construct a clinical picture that aligns with a patient’s conditions.

One of the core principles of FM is overall immune support and the ability to maintain barrier function. Even though immune system function is often measured by immune cell numbers or cytokine (inflammatory protein) concentrations in the peripheral blood, most of the activity of the immune system occurs within the various tissues and specialised organs/glands that control the interface between our bodies and the outside world. In fact, most immune system cells are found in specialised mucosal membrane barriers that make up the GI tract, respiratory tract, genitourinary tract, vagina, breast, skin, eyes and lungs. Generically, this is known as the mucosa associated lymphoid tissue (MALT).

Breaches in barrier function is one of the most threatening immune challenges a person can face in relation to their overall health as it is the initial interface between the outside world & the internal environment of the host that any pathogen or antigen has to contend with. This is why protecting barrier function, especially the integrity of the barrier within the intestinal mucosa, is vital for basic immune function and appropriate immune responses. Understanding the integrity of the gut mucosa is one of the many hallmarks & core principles of FM.

When it comes to supporting the immune system, based on the fact the 70-80% of our immune system resides there; nowhere is more critical that the GI tract. Now what makes this even more complicated is that dysfunction in any of the systems-biology elsewhere in the body effects the integrity & function of the GI tract & the immune system. To add to that; any internal or external lifestyle signals in all shapes & forms are also a factor which effect systems-biology.

Even something simple as being awake at 2am posting on social media, is causing hormone dysregulation & weakening your immune system by interrupting important metabolic activity that normally occurs between the hours of 10pm-6am. Circadian rhythm disruption is often a pretty reliable tell-tale sign of a person with underlying health conditions as so much of our systems-biology functions are synced with our closest connection to nature’s day/night rhythm, and how a healthy cortisol rhythm should align with this over a 24 hour period.

Both the innate and adaptive immune systems are critical components of the barrier function of the gut. Approximately 100 to 150 mesenteric lymph nodes are distributed throughout the gut to create numerous “stations“ for concentrated interactions between antigens, antigen-presenting cells, regulatory cells and effector cells. This specialised feature of the immune system belongs to the gut associated lymphoid tissue or (GALT), a subcategory of the mucosa associated lymphoid tissues or (MALT) that I touched upon earlier. The largest portion of GALT, where 75% of all mature immune cells are, resides in the gut.

Another special feature of the GALT is the 30 or so peyers patches found primarily along the mucosa of the final section of the small intestine known as the ileum. These peyers patches include a concentration of T-cells, B-cells and antigen-presenting cells; mostly dendritic cells, that interface directly with the gut lumen through the activities of special gut epithelial cells called M-cells (micro-fold cells). These M-cells are designed to allow the controlled passage of antigens (commensal bacteria, pathogenic bacteria, viruses, fungi, food particles, etc) into the lumen, where they can be delivered safely to antigen-presenting cells that, in turn, present them to both mature and naive T-cells.

In addition to the M-cell mediated antigen sampling, specialised dendritic cells are capable of changing their morphology to permit direct surveillance of the gut lumen by an extension protruding between the gut epithelial cells. This allows the dendritic cells to use as many pattern recognition receptors to begin reacting to changes within the “pattern” of pathogens in the car before specific antigens are presented to the adaptive immune cells. This process of immunosurveillance is considered to be an important part of “education”, “learning” and maturation of the immune system, and also provides an early warning of potential pathogenic agents in the gut, allowing for a pre-emptive response. The ultimate goal is to mount appropriate and timely immune responses to harmful and foreign antigen is well creating an active tolerance against harmless self-antigens.

One of the unique features of the adaptive immune response within the GALT, as in most other mucosal tissues, is the abundance of antibodies secreting B-cells, called plasma cells, which produce antibodies of the secretory IgA class (sIgA). This form of antibody is capable of passing into the lumen of the gut, as it does in breast milk, saliva, tears, etc, to interact with antigens with just the immune system complexes & barrier functions acting as the proverbial ‘nightclub bouncer’ that is responsible for controlling anything passing through that wants to enter the venue of the body. Put a scrawny, weak, inexperienced team of security on the door and you are guaranteed to have problems in the venue, especially if any trouble kicks off, so to speak. Think of that analogy when you think of the immune barrier function.

Antigens sampled via the the M-cells are presented to T-helper cells in the cells in them mesenteric lymph nodes and, when appropriate cross-reactivity is triggered, B-cells are activated to secrete the corresponding sIgA. sIgA expression against both pathogenic & commensal organisms is a key regulatory feature of the intestinal barrier itself which is reduced increased HPA-axis stress. sIgA is a robust marker of mucosal immune health and/or HPA axis stress induced immune suppression which can indicate a particular antigenic challenge both acute or chronic.

Breaches in the gut barrier function are one of the most potent immune challenges we can face as human beings. Intestinal permeability (leaky gut) may permit unprocessed antigens, or even intact organisms from the gut lumen, entry to the lamina propria by passing between, rather than being processed through, GI epithelial cells. These unprocessed antigens are capable of triggering immune responses that can increase the susceptibility to autoimmune cross-reactivity. Something I see a lot in FM practice.

For many years conventional medicine has rolled their eyes when they heard the term ‘leaky gut’ being talked about by FM clinicians, Naturopaths or even by some patients as a potential underlying factor to health conditions. Who can blame them for two reasons…. 1 – The term ‘leaky gut’ which sounds ‘made-up’ was a patient-friendly term to describe intestinal hyper-permeability; a dysfunction within the normal protective mechanism of the intestinal cells. And 2 – Most GP’s & MD’s believe that if something wasn’t in the medical text books that they learned from at medical school; it isn’t a real condition.

Using gluten and coeliac disease as a model, research by Fasano et al. scientifically proved a newly mediated loosening of the tight junction proteins, which are intended to prevent intestinal permeability, a model they believe defines a role for intestinal permeability in other immune system conditions such as type one diabetes, asthma, Multiple Sclerosis (MS) and inflammatory bowel disease (IBD). Although this model is being held as a groundbreaking advance to our understanding in FM on how GI disturbances of any kind can trigger an autoimmune response, it is still under considerable debate within the larger more conventional world of immunology which is no surprise as conventional medicine seems to be years behind FM and the ever evolving evidence-based research around what I class as the smartest & most nature-aligned approach to health restoration. What’s interesting is that FM clinicians like myself are having great success preventing/managing/reversing autoimmunity, and chronic health disorders using this model with natural medicine.

The GI tract represents our most intimate contact with the external environment. Over our lifetime we consume between 30 to 50 tons of food and host more microbial cells in our gut and human cells in the rest of our body. The GI tract is tasked with the responsibilities of extracting the appropriate nutrients we need to thrive, maintaining appropriate balance of helpful and harmful microbes, and acting as a conduit for waste removal. At the same time, the healthy GI tract prevents the entrance of harmful substances into the body. As a result, patients with major GI disorders will manifest symptoms that are systemic.

Removing agents that damage or aggravate intestinal cells or the immune system in the GI tract is critical to barrier function. When the GALT is challenged by the need to constantly respond to food antigens, pathogenic bacteria, toxins or other harmful agents etc, chronic inflammation will result. It is this ongoing inflammation that can lead to intestinal permeability (leaky gut), allowing antigens entry into the body (lamina propria) while avoiding the highly regulated process of M-cell sampling, further adding to immune activation.

Much like antigens such as gluten/gliadin in coeliac disease patients that need to be permanently avoided; certain immune challenging substances in non-coeliac patients with health challenges, some autoimmune in nature, may also need to be permanently removed from the diet in order to prevent/manage/restore a certain condition.

In other cases, some offending substances may be added back to the diet in moderation once the patient’s GI tract has been repaired and quieting any over excitement of the GALT.

Reducing obesity/fat mass is another important step in reducing the inflammatory load as excess adipose tissue (stored cellular body fat) produces many inflammatory cytokines which are inflammatory proteins that circulate around the body with destructive consequences in the surrounding tissues. Weight reduction, especially fat mass reduction, and improving glycaemic control (blood sugar stabilisation) will all contribute to a reduction in the inflammatory burden on the GI tract. The relationship between obesity and relative abundance of certain got microflora also suggest a direct GI mediation of obesity related inflammation.

Another thing my mentors & I have been talking about/practicing for well over a decade, that is now being talked about & universally understood in the medical community (finally), and that is that GI function and health is strongly correlated with the commensal organisms living within the GI tract (my second basic principle for immune support). The hundreds of subspecies of bacteria that reside in the gut, function in close relationship with both the barrier and immune modulating functions of the gut, protecting the host from immune disturbances in the gut and elsewhere. As mentioned previously, the “training “and maturation of immune system cells is partially dependent on continuous sampling of commensal organisms from within the got by the GALT.

The past decade has seen rapid advances in our ability to find the nature of the GI microbiota and understand the important role it plays in nearly every health condition. I made a prediction 10 years ago that the microbiome/microbiota would be one of the most researched topics in the future of science & health, which has now manifested to be true.

Research looking into interrelationships between specific commensal organisms and specific immune outcomes is still ongoing. While these types of relationships are well known for disease-causing organisms, it is now recognised that certain families and species are friendly commensal organisms are responsible for modulating the tight junctions, up regulating sIgA, hindering the growth of harmful organisms, promoting an anti-inflammatory environment, detoxifying harmful metabolites, and liberating or producing several important nutrients.

FM is always about locating the hidden cracks or weaknesses in the structure of the person, repairing & strengthening the foundations, and restoring function within the building of the body.

Almost paralleling time with the development of the Rome criteria, the paradigm of medicine that has been emerging that acknowledges all body functions (and therefore, dysfunctions) are ultimately at the source of all complex chronic disease and healing potential. This new paradigm of medicine is what is now referred to as “functional medicine”. FM essentially combines the importance of patient centred preventative care within the understanding of the complex into connections between organ systems or “systems-biology” using cutting edge science.

This form of medicine allows FM practitioners like myself to understand the complex network connecting each body system through physiology and biochemistry. No longer is each body system isolated from the another. In essence, this form of medicine asks “what are the common threads connecting the symptom pattern seen the patient experience in chronic illness?” Rather than merely “how can we differentiate one disease from another?”

The net result is a functional wellness roadmap focused on addressing dysfunctions/underlying causes of complex and chronic disease patterns that are tailored to specific patients.

This article is a small taster of the role of the GI tract plays in immunity, which becomes even more complex when you factor in the other body-systems and the impact each have on one another. If you are suffering with health issues and are looking for answers, feel free to book a free 30 minute consultation to discuss you unique situation and see if we are the right fit to work together.

Thank you for your attention.

*Steve Hawes