Leaky Gut and Autoimmunity
Medicine has a long history of establishing a standard or viewpoint and then being resistant to changing it. The landscape is evolving, however, and a good example is our growing understanding of the mechanisms and drivers of autoimmunity.
Equally as dynamic is our understanding of a condition that has now been associated with autoimmunity: leaky gut syndrome or intestinal hyper-permeability.
Remember, an autoimmune disease occurs when our immune system produces antibodies whose job is to attack what the immune system has tagged as foreign invaders. This is a wonderful survival mechanism when that foreign invader is a pathogen that could harm us. In autoimmune diseases, however, it is our own tissues that are being attacked, leading to dysfunction, deterioration and even destruction of the targeted tissues.
If the antibodies target and attack the thyroid, for example, Hashimoto’s thyroiditis or Graves’ disease can be diagnosed.
The table in the next column lists some familiar tissue antibody and disease associations:
Unfortunately, this list grows longer each year.
To date, the American Autoimmune Related Diseases Association (AARDA), a non-profit organization with the mission to raise awareness about autoimmune diseases, estimates that1 more than one hundred different autoimmune diseases have been identified, with an additional forty plus illnesses suspected to have an autoimmune component.
And in case you think that leaky gut syndrome is only understood by integrative and functional medicine practitioners, think again. The well-respected researcher Alessio Fasano, MD of Massachusetts General Hospital in Boston has brought the concept of intestinal permeability as an initiating driver in the pathogenesis of autoimmune disorders to the forefront of conventional medicine’s consciousness with his published research in many well-respected gastroenterology and immunology journals.2
How does this happen?
Our intestinal lining serves many coordinated functions; one less commonly considered is its barrier functions, which provides an interface between the external environment and our internal systemic circulation. With healthy digestion, all food is broken down into smaller particle levels for absorption. Proteins are broken down to the amino acid level, and those amino acids are allowed passage through the intestinal wall, providing building blocks that our bodies require. With leaky gut, the barrier junctions between individual intestinal cells (aka the paracellular space between enterocytes) are no longer “tight,” and proteins slip through these junctions before they are broken down fully into their amino acid components. The body cannot use these proteins, nor can our immune system identify them, so they are tagged as foreign invaders by our immune system, and the body initiates an immune and inflammatory response against them.
Molecular mimicry and autoimmunity
Molecular mimicry occurs when our immune system is exposed to specific antigens (those foreign invaders, perceived or real, mentioned earlier) and in genetically susceptible individuals, these antigens cause cross-reactions with structurally similar amino acid patterns found in human tissues.
There are a long list of firmly established associations between specific dietary derived antigens (most commonly from certain proteins in wheat (gluten) and dairy (casein), as well as pathogenic bacteria and the diagnosis of specific autoimmune disorders.
The table to the right is an expanded version of the one found on the last page. It includes the associated overgrowth of identified microbe species associated with certain autoimmune disorders where known 3.
The triad of autoimmunity
Dr. Fassano wrote an article in the lay magazine Scientific American in 2009 titled “Surprises from Celiac Disease” that I think flipped the scientific conversation of autoimmunity on its head. Dr. Fasano clearly and eloquently described his theory of leaky gut contributing to Celiac disease and autoimmunity to a lay audience; the same research that was initially greeted with skepticism by the research community.4
Dr. Fasano has proposed that for an autoimmune disease to manifest itself, there must be three variables present. He equates these three variables to a three-legged stool or the center of a Venn diagram, where if any of the three are not present the disease cannot manifest.
These three variables are:
- Genetic susceptibility (i.e., an HLA pattern that is particularly efficient at presenting the antigen to the immune system).
- An environmental trigger (i.e., antigen).
- Intestinal hyper-permeability (i.e., leaky gut syndrome).
In lectures, Dr. Fasano provides a very descriptive analogy to show how these three variables interact:
- Our genetics are the gun,
- environmental triggers load the gun,
- and intestinal hyper-permeability fires the gun.
While it was previously believed that once an autoimmune illness was activated, the process remained ongoing, with remissions and relapses, Dr. Fasano’s research suggests that the process can be modulated and possibly reversed by interrupting one of the modifiable variables of the triad. Dr. Fasano and others suggest that by far the easiest of the three variables to alter clinically is the third: intestinal permeability.
Where gluten fits into all this:
Zonulin, discovered by Dr. Fasano and his team in 2000, is a protein that modulates the permeability of the (tight) junctions between the cells lining our digestive tract. Zonulin could be considered a leakiness regulator and a biological door to inflammation and autoimmunity.
If you get food poisoning, zonulin is triggered via the immune system by the bad bacteria you ate, promoting diarrhea to flush the buggers out. Once the bacteria are gone, zonulin levels lower and the intestinal tight junctions close.
It turns out that gluten, or any one of its 50 epitopes, is a strong trigger of zonulin in some populations. No human can completely digest gluten. And for a select population that is sensitive, undigested gluten can trigger the release of zonulin. Increased zonulin levels equate to increased intestinal permeability. 5, 6
“Once gluten is removed from the diet, serum zonulin levels decrease, the intestine resumes its baseline barrier function, the autoantibody titers are normalized, the autoimmune process shuts off and, consequently, the intestinal damage heals completely.”5
Other variables that can increase zonulin and promote leaky gut include:
Bacterial or fungal dysbiosis
SIBO = small intestinal bacterial overgrowth
Effective supplemental agents commonly used to address intestinal permeability
Mucilaginous herbs (fenugreek, licorice, marshmallow root, slippery elm)
Direct acting anti-inflammatory botanicals (boswellia serrata, zingiber officinale, uncaria tomentosa, salix sp.)
Indirect-acting anti-inflammatory botanicals (oregano, berberine, artemisia)
Omega-3 fatty acids
The FOUR-Step Plan for gut health
- REMOVE foods, stress, lack of sleep and other factors that damage the gut
- REPLACE digestive enzymes and healing foods (bone broth, fermented foods, coconut products (MCFA), etc.)
- REPAIR with supplements listed above
- REBALANCE with probiotics
It is hoped that this article has provided a comprehensive framework for your understanding and approach to addressing autoimmune disorders and their relationship to intestinal hyper-permeability.
In such complex dysregulated physiological conditions, a systematic approach to treatment with time for the body to heal and adjust is required. As discussed, remember to:
Detect and eliminate food sensitivities
Focus on optimizing GI mucosal immune function and the microbiome (use the Four-Step Food Plan as a basic framework)
Identify and eradicate infectious and parasitic triggers with antimicrobial therapy
Promote an anti-inflammatory lifestyle
By Julie Beck, DC, MS CSCS
- Fasano A and Shea-Donohue T, “Mechanisms of Disease: The Role of Intestinal Barrier Function in the Pathogenesis of Gastrointestinal Autoimmune Diseases,” Nature Clinical Practice Gastroenterology & Hepatology, Vol. 2, No. 9, 2005, pp. 416-422.
- Mayes MD, “Epidemiologic Studies of Environmental Agents and Systemic Autoimmune Diseases,” Environmental Health Perspectives, Vol. 107, Supplement 5, 1999, pp. 743-748.
- Fasano A, “Surprises from Celiac Disease,” Scientific American, Vol. 301, No. 2, 2009, pp. 54-61.
- Vojdani A, “For the Assessment of Intestinal Permeability, Size Matters,” Alternative Therapies in Health and Medicine, Jan/Feb 3013, Vol 19. No.1
- Fasano A, “Zonulin, Regulation of Tight Junctions, and Autoimmune diseases,” Ann NY Acad Sci. 2012 Jul; 1258(1): 25-33