The mucosa is the inner lining of the digestive tract; a mucous membrane. The innermost layer of the mucosa is a single layer of cells called the epithelium. The epithelial cells of the digestive tract are held together in tight junctions. The tight junctions are various proteins that hold the cells together to form a tight membrane. The gut is also a lymphatic organ; the mucosa contains lymphatic tissue that detects pathogens (Tortora & Derrickson, 2007, p. 475). The lining of the digestive tract is, like our skin, a barrier that protects the interior of the body from the external world. It is, not unlike the skin, a membrane that is semi-permeable, but must block harmful substances that should not be in our bodies. If our skin is strong and healthy, it is able to impede the entrance of bacteria, viruses, and other harmful substances. In the same way, our digestive system is a semi-permeable barrier that must facilitate the passage of nutrients after they have been adequately digested, but prevent the entrance of any other xenobiotic. It is not simple like a sieve, but rather a selectively permeable membrane that intelligently allows the passage of certain nutrients while protecting the body from undesired substances.

Leaky gut is a term used for a pathology of a digestive tract that has become excessively permeable, and is not adequately doing its job of separating the intestinal contents from the inside of the body. This can be caused by damage to the enterocyte by a toxin or damaging substance. When the enterocyte is destroyed, a hole is left through which material can pass. Another factor is tight junction dysregulation, which I will discuss later. In either case, excessive amounts of undigested proteins, bacteria, and other macromolecules can pass through the epithelium and result in immune system activation. Within the mucosa, just below the epithelium are a host of immune cells, including macrophages, dendritic cells, B cells, and lymphocytes, as well as naïve T and B cells (Ballantyne, 2013, p. 50). When the body encounters these foreign substance, it triggers both the adaptive and innate immune system which responds by producing antibodies. Even normal gut flora can provoke an immune response when they leak out of the gut. When the adaptive immune system creates antibodies to an antigen, they travel throughout the body looking for something that has the same amino acid sequence that they were programmed to recognize. Unfortunately, some proteins in our own body may have similar surface proteins, so that our own body tissues are attacked. This is called cross-reactivity. Depending on the severity of leaky gut, and the particular genetic makeup, stress, and other lifestyle factors, the inflammation that results from leaky gut can result in many serious health conditions. Some clinicians suggest that low HDL levels might be a proxy indicator for leaky gut [reference needed].

Much of what is known about leaky gut has been discovered through the study of celiac disease, and gluten’s role in the disease. The Center for Celiac Research, led by Dr. Alessio Fasano, brought awareness to the prevalence of celiac disease, and investigated the mechanisms involved in its pathology. The research discovered zonulin, a molecule that is responsible for mediating tight junctions. Gluten was found to trigger the release of zonulin, and zonulin triggered intestinal permeability, which triggers the disease:

…When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability that was blocked by FZI/0 pretreatment. Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (CD) tissues. Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression. Conclusions. Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules. (Fasano, et al., 2006)

In a later publication, Dr. Fasano et al. postulated that intestinal permeability, as well as environmental factors and genetics, is a precursor in the development of all autoimmune diseases (Visser, Rozing, Sapone, Lammera, & Fasano, 2009). This would incriminate wheat and other gluten containing grains as being contributors to a plethora of modern diseases. Sarah Ballantyne goes so far as to say that “…by healing a leaky gut you can reverse autoimmune disease!” (Ballantyne, 2013, p. 48) It sounds easy in theory, but in practice the solution is more elusive.

This notion of leaky gut being responsible for autoimmunity is helping to propel the modern low carbohydrate and gluten free diets into the mainstream. However, the conclusion from Dr. Fasano’s research is only that gluten is a trigger for autoimmunity by increasing intestinal permeability, not that it directly causes any disease in absence of other risk factors. For example, exercise could trigger an asthma attack, but that doesn’t mean that it made the person sick in the first place. This is why I’m not putting all the blame on gluten. The regulation of the tight junctions by the epithelial cells is not well understood, and I opine that we should not conclude that mild up-regulation of zonulin from consuming a natural, whole-foods diet would be detrimental for a healthy person. On the other hand, most of us do not eat a natural whole-foods diet, and our modern wheat has been highly modified from its natural form, is sprayed with herbicides and other chemicals. Furthermore, many of us are living with digestive systems that are already in some state of disrepair, whether from foods, environmental chemicals, or other reasons, so avoiding wheat and other gluten-containing foods is probably a good idea for most people.

Leaky gut results from many factors. Some identified factors include:

• Stress (physical or emotional) can weaken the mucus layer and decrease blood flow to the gut by altering the balance of the autonomic nervous system. The body’s ability to digest food decreases when a person is feeling stress or anxiety (Minocha, 2014, p. 67). It’s advisable to not eat when you’re in a stressful situation. Chronic stress is indicated by muscle loss.
• Toxins can cause leaky gut by various mechanisms. They can directly damage gut enterocytes, or cause damage by other mechanisms. Many common medications can do serious damage to the gut, especially when used long-term. NSAIDs block cyclooxygenase (COX), a class of enzymes that are necessary for maintaining the integrity of the gut layer. Also, NSAIDS trigger the adherence of leukocytes to the vascular endothelium, and block prostaglandins, which are needed to maintain adequate blood flow to the gut to facilitate healing. (Wallace, 2008)
• GMOs – Genetically modified foods have toxins, and proteins that may cause inflammation in the gut. Genetically engineered varieties of grains contain higher levels of prolamins and agglutanens, which are brutal to the digestive system.
• Mold, or a reaction to mycotoxins could manifest as leaky gut.
• Oxalates. Some people have lost the ability to detoxify oxalates, and these damage the digestive tract. See my article on this topic. Glyphosate destroys gut bacteria that break down oxalates, leading to a sulfur deficiency. Low sulfur impairs the formation of the mucus lining. (Rostenberg, 2016)
• Alcohol opens tight junctions, depletes B vitamins, depletes glutathione, and feeds Gram-negative bacteria, causing an increase in endotoxins.
• Pathogens, including parasites or bacteria such as Helicobacter pylori produce endotoxins which increase gut permeability. (O’Dwyer, et al., 1988) The presence of a pathogen will increase the production of cortisol. H. pylori can result in inflammation of the gut mucosa and a destruction of cells lining the gut, but some people have no GI symptoms at all, only fatigue. An infection can mimic the symptoms of GERD or IBS and results in poor protein digestion, which can result in amino acid imbalances. H. pylori can cause either too much or too little stomach acid, depending on the location of the infection.
• Poor diet causes disease. Unhealthy fats can result in inflammation. Certain lectins which are found in grains and legumes can be damaging to the gut, particularly prolamins, agglutinins, and saponins. Our digestive enzymes are not very good at breaking them apart, so and they can result in feeding bacteria instead (Ballantyne, 2013, p. 54). Nightshade vegetables including potatoes contain varying levels of glycoalkaloids, which can harm epithelial cells. Modern wheat should be totally avoided by anyone wanting to improve their digestive health.
• Allergies and food sensitivities can cause an immune response to food, which can exacerbate the damage to the gut, which conversely increases the immune response in a viscous cycle.
• Cooking foods at high temperatures destroys nutrients and makes it more inflammatory. Advanced glycation end products (AGES) contribute to the elevated immune response. (Minocha, 2014)
• Sugar feeds yeast, causing candida and yeast overgrowth.
• Elevated levels of cortisol, blood sugar, and certain other hormones open tight junctions and divert blood away from digestion.
• Liver problems. The liver is responsible for detoxification, and for the synthesis of hormones and bile.
• Nutritional deficiencies hinder gut repair. The cells lining the gut have a very fast turnover rate, and for a new cell to be formed, many nutrients must be present. A deficiency of vitamins, minerals, or various other co-factors will degrade gut health. Particularly important are Vitamin A and Vitamin D. Unfortunately an inflamed gut lining will cause malabsorption (because of excess mucus, or damaged enterocytes), which can make it more difficult to heal.
• Leaky gut and inflammation can exist together in a viscous cycle, and inflammatory molecules affect the entire body. This is mostly due to a molecule called lipopolysacchride (LPS), which is found in the cell membranes of Gram-negative bacteria. Leaky gut will allow this toxin to enter the bloodstream, affecting the entire body. This is partly why leaky gut can trigger autoimmune disease. The inflammation in the gut will eventually result in a leaky blood-brain barrier.
• Exercise causes a decrease in blood flow to the gut, since energy is being diverted to other parts of the body, although exercise has other benefits that promote general health. Some people feel better after exercise due to the rush of cortisol, and other hormones. It is generally recommended to abstain from strenuous exercise immediately after eating, and to stay adequately hydrated.
• Lack of beneficial bacteria, due to excessive hygiene, environmental chemicals, and antibiotics. The herbicide glyphosate is directly toxic to the gut bacteria, and is becoming ubiquitous in the environment. Gut bacteria produce certain vitamins, neurotransmitters, as well as create short-chain fatty acids. Those who are nonsecreters of ABO group are more likely to have severely disrupted gut microbiome (Peter D’Adamo). Antibiotics decimate gut bacteria.
• Low serum folate will lead to unstable gut flora. (Stirling Hill)
• Pasteurized milk is irritating to the gut lining, and promotes inflammation, while raw milk may have a protective effect. (Shanahan & Shanahan, 2009, p. 159) (Minocha, 2014, p. 61) Milk is a common allergen, so a person with gut problems might need to avoid it. Conventional dairy contains antibiotics, and a lot of nasty chemicals. A1 casein might cause problems.
• Lack of good sleep makes it difficult to heal. (Lipski, 2012, p. 174)
• Poor brain health results in a decreased activation of the vagus nerve. Reduced vagal function results in poor blood flow, reduced motility, low HCl and enzyme secretion, and can lead to overgrowth of bacteria and yeasts. (Kharrazian, 2013, p. 168)

Depending on the severity, leaky gut is very difficult to treat, and requires a multifaceted approach that identifies and treats the root causes, while also addressing other factors, including stress, good sleep, allergies, food sensitivities, brain health, immune system inflammation, malabsorption, endocrine function, infections, and genetics.

Bibliography

Ballantyne, S. (2013). The Paleo Approach. Victory Belt Publishing Inc.

Fasano, A., Drago, S., El Asmar, R., Di Pierro, M., Grazia Clemente, M., Anna Sapone, A. T., . . . Catassi, C. (2006). Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scandinavian Journal of Gastroenterology.

Kharrazian, D. (2013). Why Isn’t My Brain Working? Elephant Press.

Lipski, E. P. (2012). Digestive Wellness. McGraw-Hill.

Minocha, A. (2014). Is It Leaky Gut or Leaky Gut Syndrome? Shreveport: LOGOS Enterprises LLC.

O’Dwyer, S., FRCS, Michie, H., Ziegler, T., Revhaug, A., Smith, R., & Willmore, D. (1988). A Single Dose of Endotoxin Increases Intestinal Permeability in Healthy Humans. Retrieved from Jama Surgery: http://archsurg.jamanetwork.com/article.aspx?articleid=593588

Rostenberg, A. (2016 March 21) The Down Side To High Oxalates http://www.beyondmthfr.com/side-high-oxalates-problems-sulfate-b6-gut-methylation/ Beyond MTHFR

Shanahan, C., & Shanahan, L. (2009). Deep Nutrition – Why Your Genes Need Traditional Food. Lawai, HI: Big Box Books.

Tortora, G. J., & Derrickson, B. (2007). Introduction to the Human Body. New York: John Wiley & Sons, Inc.

Visser, J., Rozing, J., Sapone, A., Lammera, K., & Fasano, A. (2009). Tight Junctions, Intestinal Permeability, and Autoimmunity – Celiac Disease and Type 1 Diabetes Paradigms. Annals of the New York Academy of Sciences, 1.

Wallace, J. L. (2008, October 1). Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn’t the Stomach Digest Itself? Retrieved from Physiological Reviews: http://physrev.physiology.org/content/88/4/1547