Intestinal Permeability, A.K.A. “Leaky Gut” - What is it & What Causes it?

“All disease begins in the gut.” - Hippocrates

How often do we feel like we’re just “getting by” – lethargic, run-down, and torpid?  It seems every day I speak to people living this way, whose doctors are equally baffled by a slew of symptoms whose tests show “nothing is wrong.”  Medication is given regardless, which is not only ineffective, but results in more side effects, continuing the perpetual cycle of surviving rather than thriving.  So what’s happening? 

Chronic fatigue, headaches, digestion issues, depression, anxiety, joint pain, inflammation, food sensitivities, thyroid and autoimmune conditions plague numerous people.  Rather than addressing the root cause, however, our doctors simply prescribe medication to treat the symptom: the Band-Aid approach.  Psychiatrists “treat” depression with SSRIs, rheumatologists “fix” arthritis or joint inflammation with steroids, and gastroenterologists “solve” GERD with a protein pump inhibitor, right? Wrong.  None of these things are solving THE problem.

In an attempt to bridge this gap between root cause and temporary solution, more and more people are turning to their own research and looking for doctors who can support the same.  If we can possibly uncover where these chronic symptoms and conditions originate, we can allow the body to fix itself without the side effects and limited success of pharmaceuticals. 

This article employs scientific research to provide insight into one of society’s chronic disease states.  It’s a growing epidemic that may be the cause behind that constant feeling of running on 2 cylinders rather than a full 6-8.  This epidemic is called “Leaky Gut”.

Despite its widespread effects, Intestinal Permeability, colloquially known as “Leaky Gut”, has not yet been given credence by the Western medical society.  I challenge you to ask yourself why.  There are literally thousands of research articles on the subject since the early 80’s, but modern pharmaceuticals and their research continue to take the forefront in terms of allopathic care.  

Although pharmaceutical companies’ vast resources provide a greater stage for medical research, there are inherent problems within the scope of this research as well as the ethics behind it.  Pharmaceutical focus is on large clinical trials of end stage disease and medication rather than the antecedent of disease.  These large companies spend billions to provide research for promoting a new drug.

The financial relationship between pharmaceutical companies and the physicians participating in their research creates bias and conflict of interest, yet this is where our medical system turns to most for answers.   And, society as a whole generally trusts a doctor’s plan of care because of his or her expertise and credentials. (23)(21) Furthermore, due to less insurance reimbursement, doctors have limited time to see their patients and do their own research beyond their specialty.  From a cost/time standpoint how can our doctors truly evaluate holistically? We, as patients, are moved quickly through a system that matches diagnosis to medication rather than seeking the problem’s pre-curser.  When thyroid levels are “off “, for example, what might be happening downstream of that? What are the ferritin, iodine, and magnesium levels and why are they out of range?  Or perhaps a patient feels terrible most of the time but all lab reports are within “normal range.” The current medical paradigm is based on treating (or not treating) lab results rather than looking at the whole person.  It is imperative that we take control of our own health.   We must educate and help ourselves by questioning the current “solutions”, and researching more mindfully to ensure a healthier future.

What is “Leaky Gut”?

 “Leaky Gut” occurs when small openings pervade the small intestine.  Large food particles, bacterial wastes, and environmental toxins then pass through the intestinal wall and exist where they normally would not.  This causes an inflammatory and immune response, possibly creating the right environment for an autoimmune condition to develop.

Why are these holes created in the first place?

Many theories explain what might predispose one to these leaky holes. 

1. Gluten- Increased consumption of super-hybridized gluten (a protein found in wheat products). Gluten is excessively used throughout our food supply, which is drastically different than it was just 60 years ago.  It is pervasive - in everything from bread to salad dressing, leading to its mass consumption.  Because it has been hybridized to withstand the environment better and provide a larger food source for the world, its proteins are unrecognizable in the body and not all of these proteins have even been verified by the FDA. (9) These new proteins do not discriminate.  Gliadin, one of the proteins in gluten that triggers the immune response in celiac patients, “causes intestinal permeability in both celiac and non-celiac intestinal mucosa”. (10)

2.  Excessive Stress- Research has shown that both physical and emotional stress can cause leaky gut.  Long distance running, for example, can alter the gut flora and increase intestinal permeability. (20) According to one study, stress increases intestinal permeability and can cause digestion to slow down (constipation) or speed up (diarrhea) as well as start an inflammatory response.  In conclusion,  “stress increases intestinal permeability, visceral sensitivity, alteration in G.I. motility and leads to profound mast cell activation resulting in the release of pro-inflammatory mediators”. (17) Furthermore, most patients seeking medical consultation for gastrointestinal problems often have an associated affective disorder like anxiety or depression. (1)

Luckily, the damage may be reversible. One particular study demonstrated that when the gut flora in mice was directly manipulated, their behavior changed.  Specifically, when good bacteria were re-introduced, the mice exhibited less anxiety and more confident behavior.  This suggests that the gut brain connection is bi-directional: the gut affects the brain and vice versa. (4)

The practical application of this means that rebalancing your gut by increasing good bacteria is critical for physical and mental health.   Prebiotics and probiotics may be particularly useful in restoring the balance of the microbiome. (24) In addition, physical and mental stress reduction techniques are essential components of any treatment plan to help promote healing and maintenance of a healthy gut.  This is, however, by no means a cure-all.  As first mentioned, it is imperative to find the root cause of the leaky gut before taking strides to heal it.

3.  Increased and Long-term Use of Antibiotics, NSAID’s and Aspirin

Antibiotics alter the gut microbiome.  There are numerous articles on the problems with long-term use of antibiotics.  These medications are not, unfortunately, selective in the bacteria they target: both good and bad bacteria are killed.  The absence of good bacteria results in an overgrowth of bad bacteria, altogether altering the microbiome of the gut and disrupting the balance of the entire body.  When gut flora is not balanced due to antibiotic use, bacteria that are normally found only in the large intestine can back up into the small intestine and cause problems such as leaky gut.  It can also cause small intestine bacteria overgrowth (SIBO) and candida (an overgrowth of yeast in your intestines) both deserving more detail in a future paper.  A good balance of bacteria is so beneficial to health we are now even successfully treating difficult cases of C. dificile with donor feces. (5)  

NSAIDS and aspirin- Beyond antibiotics, regular use of Non-Steroidal Anti-Inflammatories (NSAIDs) and aspirin can cause leaky gut.  In fact, many studies agree that all conventional NSAID’s increase intestinal permeability within 24 hours, and worse if taken long term. (3) Knowing this, why is history of over the counter medications and antibiotic use not regularly part of the medical evaluation?  Perhaps we should think twice before mindlessly popping a Motrin and, at the very least, conjointly utilize probiotics or probiotic rich foods to optimize gut flora conditions.

4.  GMO’s and environmental toxins

So much has been written about genetically modified organisms (GMOs) and their impact on our health.  GM foods have been shown to have a direct effect on gut environment and immune response.  In a study done feeding mice GM corn, allergic and inflammatory markers were increased, more significantly in the very young and the old mice than in the control groups. (14) The application here is that the underdeveloped or compromised gut may be much more susceptible to insult.   Shouldn’t we therefore be especially prudent when considering the diet of our children and those populations with already compromised gut flora?  Could this be one of the reasons contributing to the growing epidemic of food allergies?

5.  Diet low in probiotics and fiber, high in sugar and processed foods

 Diet and the foods we eat strongly influence the composition of the gut environment. (16)(6) One study indicates that “diet has a dominating role in shaping gut microbiota and changing key populations may transform healthy gut microbiota into a disease-inducing entity”. (6) High amounts of sugar or processed food in the diet will feed the pathogenic bacteria causing an overgrowth.  According to the USDA dietary guidelines, the typical American diet is extremely low in fiber (18) and a high fiber diet has been shown to help prevent the overgrowth of pathogenic bacteria such as E. Coli. (6) 

We can improve this environment by decreasing overall sugar consumption and increasing probiotics and probiotic rich sources, like fermented foods.  In fact, a Stanford study looking at the effects of probiotics after gastric bypass surgery found that not only did the subjects lose more weight, but also their vitamin B12 levels increased by 67%! (25)

How does the small intestine become leaky once exposed to these conditions?

 Dr. Alessio Fasano, a globally renowned researcher recognized for his work with celiac disease and gluten intolerance, accidentally discovered the cause of intestinal permeability in 2000.   While researching a cure for cholera, he and his colleagues discovered the molecule “zonulin,” which is responsible for initiating the opening of the tight junctions between the cells lining the small intestine.   According to Fasano, there are 2 major stimuli causing the release of zonulin and its prospective cascade of events: bacteria and gluten.

1.  Bacteria

When bacteria back up from the large intestine and become more populated in the small intestine, they begin “stealing” nutrients to survive and multiply.  This results in the small intestine’s failure to absorb critical elements needed by the body.  Might this explain why low levels of magnesium, iron or B12 persist on our lab tests in spite supplementation? 

The epithelial cells (which line our intestines) recognize these bacteria as foreign and release large amounts of zonulin.  The space between the cell wall opens, allowing water to enter and flush out the foreign bodies.  The immune system now becomes on alert and may produce anti-bodies to attack the foreign substances.  This creates an inflammatory and possibly an autoimmune reaction.  Fasano theorizes that when these molecules penetrate the small intestine, they may lodge themselves in different areas of the body, manifesting in a variety of ways – arthritis in the joints, MS in the brain, or Hashimotos in the thyroid. (12)(13) Dr. Alessio Fasano states that  “when the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extra-intestinal autoimmune, inflammatory, and neoplastic disorders can occur”. (11) 

2.     Gluten

Before discussing Dr. Fasano’s research, it is first important to note the distinction between celiac disease and gluten sensitivity in terms of inflammation and immune responses. There can be similar symptoms in people with gluten sensitivity as those with celiac disease, just without damage to the small intestine. Ultimately, gluten can evoke the same response in both types of individuals and can create an inflammatory reaction without becoming a more intense autoimmune response. 

 According to Dr. Fasano, the second stimulus is gluten and its associated protein gliadin.  He states that gluten induces intestinal permeability in everyone.  When introduced to the epithelial cells in the small intestine, zonulin is again released.  The junctions between the cells then open, allowing gluten to pass through the small intestine.  In a person that does not have celiac, this opening and shutting of the cell wall is relatively short, only minutes long, which may still provoke an inflammatory reaction but not a full blown autoimmune response. (8) In someone with celiac, however, the opening of the gates is much longer, allowing more gluten and other molecules from the environment to leak through, causing the immune system to be on full alert.  The body then mounts an immune response against this perceived threat, damaging the cell walls and ultimately leading to celiac disease.(13) 

What issues can result from this faulty opening?

 The body perceives the molecules that are now outside of the intestinal wall as a threat.  The immune system is activated, causing inflammation and, if continued long enough, the start of chronic disease. It can wreak havoc throughout the entire body and masquerade as other illnesses and symptoms, including:

Gut conditions: Irritable bowel, weight loss resistance, constipation, diarrhea, bloating, heartburn, gas, burping

Skin Symptoms: Itchy skin, hives, rashes, eczema, psoriasis, acne, rosacea. 

Brain Symptoms:  brain fog, depression, anxiety, ADHD, chronic headaches.  

In the gut there are a wide range of hormones and around 40 neurotransmitters of the same classes as those found in the brain. Gut bacteria also produce hundreds of neurochemicals that the brain uses to regulate basic physiological processes as well as mental processes such as learning, memory and mood. Intriguingly, about 95% of the serotonin present in the body, one of the brain’s important neuro-transmitters, is manufactured in the gut. (7) Taking this into consideration, might it be useful to include gut function in a mental health evaluation?

Autoimmune disease- According to the National Institute for Health over 25 million people have been diagnosed with autoimmune disease, which is now more prevalent in the U.S. than cancer. (2) (22) In a literature review of 121 articles on PubMed and SciELO (The Scientific Electronic Library Online), researchers found the use of probiotics helped decrease intestinal permeability by reducing the inflammatory response and oxidative stress. (16) These effects were shown to increase insulin sensitivity and reduce autoimmune response.  The above findings provide evidence that improving the gut microbiome with probiotics may be effective in the prevention and management of Type 1 and Type 2 Diabetes.

As evidenced above, not all leaky gut problems have gut related symptoms.  In fact, nearly 30% of those people with Leaky Gut DO NOT have any gastrointestinal problems, so they are not even aware they have it until diagnosed with another condition.  Even Hippocrates, one of most outstanding figures in the history of medicine, said, “All disease begins in the gut.”

In conclusion, the research gives us clear evidence of the existence and mechanism of intestinal permeability as well as disease states resulting from this condition.  We see that when the gut microbiome is altered, whether from bacteria, stress, toxins or food, a chain of events is triggered possibly leading to chronic physical and/or psychological disease.  We may be more or less at risk for disease when these triggers combine with our genetic codes.   

Looking forward, we need to do a better job examining our past histories of medications and over the counter drugs as well as nutrition and lifestyle.  The research strongly outlines the risks involved in taking antibiotics and use of GM foods for instance, especially in those that are immuno-compromised already.  This is not saying that antibiotics are bad, just that we need to be more cognizant of their effects, especially when used long term.  And when we really do need them, we need to take the means necessary to restore gut balance. If sources say between 70- 80% of our immune system is located in our gut, why is this not given the respect it deserves as a place to start in autoimmune disease?   It’s time to start looking at the whole person, beyond the traditional lab tests to see how all systems are working together, rather than in isolation of one another. We must be more mindful of the triggers in a person’s medical history, and these are the issues that should be addressed first.

Hopefully this brings to light a better understanding of Intestinal Permeability or “Leaky Gut”, how it occurs and what it can cause.  This report is by no means all encompassing but I encourage you to continue to look deeper, do your own homework, and challenge the thought process in your own care.   

Works Cited

(1) Addolorato, G., Mirijello, A., D’Angelo, C., Leggio, L., Ferrulli, A., Abenavoli, L., Vonghia, L., Cardone, S., Leso, V., Cossari, A., Capristo, E., Gasbarrini, G., (2008). State and trait anxiety and depression in patients affected by gastrointestinal diseases: Psychometric evaluation of 1641 patients referred to an internal medicine outpatient setting. Int J Clin Pract, 62(7): 1063-1069. Doi: 10.1111/j.1742-1241.2008.01763.x

 (2)Autoimmune Diseases. (2015, August 25). Retrieved March 6,    2015, from http://www.niaid.nih.gov/topics/autoimmune/understanding/Pages/QuickStats.aspx

(3) Biarnason, I. & Takeuchi, K. (2009). Intestinal permeability in the pathogenesis of NSAID-induced enteropathy. Gastroenterology, 44(23-29. doi: 10.1007/s00535-008-2266-6.

(4) Borre, Y.E., Moloney, R.D., Clarke, G., Dinana, T.G., & Cryan, J.F. (2014). The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. Advances in Experimental Medicine and Biology, 817, 373-403. doi: 10.1007/978-1-4939-0897-4_17.

(5) (FMT) in treatment of C. difficile infection. American Journal of Gastroenterology, 108(2): 177-185. Doi: 10.1038/ajg.2012.450

(6) Brown, K., DeCoffe, D., Molcan, E., & Gibson, D.L. (2012). Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients, 4(8) doi:  10.3390/nu4081095

(7) Carpenter, S. (2012). That gut feeling. American Psychological Association, 43(8).

(8) Daulatzai, M.A. (2015). Non-Celiac Gluten Sensitivity Triggers Gut Dysbiosis, Neuroinflammation, Gut-Brain Axis Dysfunction, and Vulnerability for Dementia. CNS Neurol Disord Drug Targets

(9) Davis, William.  Wheat Belly: Lose the Wheat, Lose the Weight, and Find Your Path Back to Health. Emmaus, Penn.: Rodale, 2011.

(10) Drago, S., El Asmar, R., Di Pierro, M., Grazia Clemente, M., Tripathi, A., Sapone, A., Thakar, M., Iacono, G., Carroccio, A., D’Agate, C., Not, T., Zampini, L., Catassi, C., Fasano, A. (2006). Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenerol. 41(4): 408-419.

(11) Fasano, A. (2011). Zonulin and its regulation of intestinal barrier function. The biological door to inflammation, autoimmunity, and cancer. Physiological Reviews, 91(1), 151-175 doi:10.1152/physrev.00003.2008

(12) Fasano, A. & Shea-Donohue, T. (2005). Mechanisms of disease: The role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nature Clinical Practice Gastroenterology & Hepatology, 416-422.doi:10.1038/ncpgasthep0259   

(13) Fasano, A. (2012, August 8). RHR: Pioneering Researcher   Alessio Fasano M.D. on Gluten, Autoimmunity and Leaky Gut. (Audio Podcast).  Retrieved from http://chriskresser.com

(14) Finamore, A., Roselli, M., Britti, S., Monastra, G., Ambra, R., Turrini, A., & Mengheri, E. (2008). Intestinal and peripheral immune response to MON810 Maize ingestion in weaning and old mice. JAgricfoodChem. http://pubs.ac.org,

(15) Gomes, A.C., Bueno, A.A., de Souza, R.G.M., & Mota, J.F.  (2014). Gut microbiota, probiotics and diabetes. Nutrition Journal, 13(60). doi:  10.1186/1475-2891-13-60

(16) Graf, D., Di Cagno, R., Fak, F., Flint, H.J., Nyman, M., Saarela, M., & Watzl, B. (2015). Contribution of diet to the composition of the human gut microbiota. Microbial Ecology in Health and Disease, 4(26), doi: 10.3402/mehd.v26.26164.

(17) Konturek, P.C., Brzozowski, T., & Konturek, S.J., (2011). Stress and the gut: Pathophysiology, clinical consequences, diagnostic approach and treatment options. Journal of Physiology and Pharmacology, 62(6): 591-599.

(18) Millen, B. (2015, February 1). Scientific Report of the 2015 Dietary Guidelines Advisory Committee.

(19) Nouri, M., Bredberg, A., Westrom, B., Lavasani, S. (2014). Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells. PLoS One, 9(9). doi: 10.1371/journal.pone.0106335.

(20) Pals, K.L., Chang R.T., Ryan, A.J., Gisolfi, C.V., (1985). Effect of running intensity on intestinal permeability. Journal of Applied Physiology, 82(2): 571-576. 

(21) Sah, S. & Fugh-Berman, A. (2013). Physicians under the Influence: Social Psychology and Industry Marketing Strategies. Journal of Law, Medicine and Ethics, 14(3).

(22) Surveillance, Epidemiology, and End Results ProgramTurning   Cancer Data Into  Discovery. (n.d.). Retrieved March 6, 2015, from  http://seer.cancer.gov/statfacts/html/all.html

(23) Thomas, H.T., Chua, G., O’Rourke, K., & Detsky, A.S. (1998). Conflict of Interest in the Debate over Calcium-Channel Antagonists. New England Journal of Medicine, 338, 101-106. doi: 10.1056/NEJM199801083380206

(24) Vitetta, L., Briskey, D., Alford, H., Hall, S., & Coulson, S. (2014). Probiotics, prebiotics and the gastrointestinal tract in health and diseases. Inflammopharmacology, 22(3), 135-154.  doi: 10.1007/s10787-014-0201-4.

(25) Woodward, G., Encarnacion, B., Downey, J.R., Chong, Hernandez-Boussard, T., & Morton, J.M. (2009). Probiotics improve outcomes after Roux-en-Y gastric bypass surgery: a prospective randomized trial.  Journal of Gastrointestinal Surgery, 13(7), 1198-204. doi: 10.1007/s11605-009-089-x.