Intestinal Permeability

Intestinal Permeability/ Leaky Gut

In the next few articles we will take a hard look at the most common disorders of the intestinal tract, with a focus on the physiologic mechanisms that lead to these disorders and how they can be corrected with natural compounds and dietary changes.  We will start this section by examining the literature on a topic that is gaining a lot of attention in gastroenterology research as well as the field of immunology: intestinal permeability or “leaky gut”.  Let’s start by explaining exactly what this condition refers to.

healthy-gut-liningWhat is Leaky Gut?

The lining of the gastrointestinal (GI) tract is composed of small epithelial cells that lie side-by-side each other forming tight junctions. These tight junctions act as a barrier between the interior of the body (blood/circulatory system) and the exterior of the body (the lumen of the GI tract).   There are two primary functions of the epithelial lining of the GI tract: the first is to absorb small micromolecules, such as digested food particles, which are used as fuel sources and other processes for the body. These micronutrients are absorbed directly into the epithelial cells or between the cells and enter the bloodstream after passing through the gut-associated lymphoid tissue (GALT), the underlying intestinal immune system.  The GALT serves as a containment system, preventing potentially harmful antigens from reaching systemic circulation.

LEAKY-GUT-SYNDROME-HEALTHY-UNHEALTHY-EPITHELIAL-CELLS“A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism.”[275]

The second function of the epithelial lining of the GI tract, is to act as a barrier and prevent the absorption of larger macromolecules which should not normally penetrate through the intestinal barrier. When the tight junctions (TJs) of the intestinal mucosa are compromised, they become widened and permeable to large undigested food compounds, toxins and bacteria.  This is known as intestinal permeability or “leaky gut”. The larger compounds of absorbed yet undigested proteins are reacted against by the immune system of the gut, called the GALT (gut-associated lymphoid tissue). This reaction then promotes exaggerated immune responsiveness and intestinal inflammation.

leaky-gutThink of the cells of your intestinal lining, where absorption of micromolecules takes place, as bricks which sit side by side along the basement membrane. These “bricks” are held together by proteins that form the tight junctions (TJs), which act as the “mortar” between the bricks. Micronutrients are absorbed into the epithelial cells and transported through the cells and basement membrane where they enter the bloodstream. If the “mortar” starts to break down, you get penetration of foreign molecules through the intestinal barrier which can then enter the bloodstream (hence the term “leaky gut”).

Sometimes the epithelial cells, or “bricks” themselves, start to break down allowing passage of toxins through the cells (transcellular passage) into the blood.  These foreign molecules may include undigested food molecules, toxins or bacteria.

Intestinal Permeability Leads to Systemic Inflammation

pathogenesis-leaky-gut-autoimmune-connectionIf anything penetrates through this gastrointestinal barrier that is foreign, the immune system is activated to eliminate or destroy these unwelcome molecules. This activation of the immune system leads to an inflammatory response. If you look at the anatomy of the intestinal lining, it is mostly immune cells with a thin layer of epithelial cells protecting it. If that epithelial layer gets breached, there is no question there will be an inflammatory immune response. So it is no surprise to see systemic inflammation and risk of autoimmunity when there is breach of this thin epithelial lining.

Increases in inflammatory responses increase risk of all chronic disease, including depression and neurodegenerative diseases, cardiovascular disease, bone loss, autoimmune disease, inflammatory bowel disease and chronic pain.  A person’s intestinal barrier integrity will influence their inflammatory load and their potential for deteriorating mechanisms throughout the body.

leaky-gut-syndromeHealth Conditions Associated with Leaky Gut Syndrome

The following conditions have been associated with leaky gut syndrome:

  • Autoimmune disorders
  • Multiple food sensitivities
  • Multiple chemical sensitivities
  • Chronic fatigue syndrome
  • Heart failure
  • Depression
  • Chronic inflammatory conditions
  • Chronic pain
  • Inflammatory bowel disease (IBD)
  • Chronic yeast overgrowth syndromes
  • Brain fog

things-you-may-not-know-autoimmune-diseaseIntestinal Permeability and Autoimmune Disease

There is a growing amount of evidence establishing the connection between intestinal permeability and the development of autoimmune disease.  This review paper was published in 2009 in the prestigious Annals of New York Academy of Science.  This journal is one of the top-rated most powerful scientific journals available:

“There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases. Therefore, we hypothesize that loss of intestinal barrier function is necessary to develop autoimmunity.”[276]

leaky-gut-progressionBasically, what this paper is saying, is that the research is pointing to intestinal permeability, or leaky gut, as a precondition for the development of all autoimmune disease, such as type I diabetes, rheumatoid arthritis (RA), lupus (SLE), multiple sclerosis (MS), Lou Gehrig’s disease (ALS), Hashimoto’s hypothyroidism, Grave’s disease, Crohn’s disease, ulcerative colitis, Celiac disease, and hundreds of other diseases.

Here’s another paper supporting this discovery:

“Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. When the finely-tuned trafficking of macromolecules is dysregulated in individuals, both intestinal and extraintestinal autoimmune disorders can occur.”[275]

gut-autoimmune-connectionOne of the hallmarks of a healthy immune system is immune tolerance to self-tissue. This prevents our immune system from attacking one’s own tissue of the body.  We are born with an immune system that is able to differentiate self-tissue from foreign pathogens and does not attack self-tissue under normal circumstances.  One of the things the research is showing is once these tight junction proteins get compromised, there is such immune zealousness and activation, this whole immune self-tolerance is lost and the immune system is prone to attacking self-tissue. When this occurs, any tissue is up for grabs for autoimmune destruction. The type of tissue that is targeted for destruction determines the type of autoimmune disease that develops.

Symptoms of Intestinal Permeability

leaky-gut-symptoms-womanSymptoms of intestinal permeability vary significantly and have a varied presentation. There is a spectrum of severity of intestinal permeability from mild to severe forms.  Here is a list of the most common symptoms associated with intestinal permeability:

  • Bloating
  • Poor Digestion
  • Inflammation
  • Food Sensitivities
  • Chronic Pain
  • Brain Fog/Poor Memory
  • Depression
  • Fatigue

symptoms-gluten-sensitivityPeople with intestinal permeability will often react to certain types of foods, especially common food allergens such as wheat and dairy. Gluten sensitivity is very common with these people. Digestive abnormalities such as gas, bloating and food sensitivities are common symptoms of leaky gut.  On the other side of the scale are people who never have intestinal symptoms but have other symptoms of chronic inflammation such as chronic pain, depression, brain fog or fatigue. They are too tired or in too much pain to go to the gym and exercise on a regular basis.  When we see patients that present with these symptoms, we have to consider intestinal permeability issues.

digestive-disordersCommon Imbalances Associated with Leaky Gut

There are a number of common imbalances that often occur together with leaky gut. These include:

  • Malabsorption/malnutrition
  • Bacterial/yeast overgrowth/dysbiosis (imbalance of beneficial and pathogenic bacteria)
  • Intestinal lining degeneration/impaired intestinal immune integrity
  • Immune activation/immune dysregulation/autoimmunity
  • Food sensitivities

medicationsMechanisms Leading to Leaky Gut

There are many different environmental and dietary factors that may damage the epithelial lining of the GI tract, including a diet high in refined sugar, intake of food allergens, such as wheat and dairy, alcohol use, use of medications such as antibiotics or NSAIDs, such as ibuprofen and aspirin, stress, chronic infections, nutrient deficiencies, hormonal deficiencies (thyroid, estrogen or testosterone) and metabolic disturbances, such as diabetes or pre-diabetes.[277-286]  All of these factors have been shown to contribute to intestinal permeability.

Alterations in intestinal physiology may affect the integrity of the intestinal epithelium tight junction protein structures.  These mechanisms basically include physiological shifts that induce greater ongoing catabolism (breakdown) versus anabolism (buildup) of the epithelial mucosa.  Additionally, systemic inflammation, which occurs in autoimmune conditions, promotes leaky gut.  So this becomes a vicious cycle of leaky gut, leading to systemic inflammation, leading to further leaky gut.

what-causes-leaky-gut-syndromeWhat are the Causes of Leaky Gut?

  • Diet (refined sugar, wheat, dairy, etc.)
  • Medication (antibiotics, NSAIDs, etc.)
  • Infection (bacterial, viral, parasitic)
  • Stress
  • Hormonal Imbalances (thyroid, estrogen, testosterone, etc.)
  • Neurologic Issues (stroke, brain injury, etc.)
  • Metabolic Issues (diabetes, pre-diabetes, etc.)
  • Autoimmunity

Assessment of Intestinal Permeability:  Intestinal Permeability Antigenic Screen

intestinal-barrier-integrity-screenThe Cyrex Labs Array 2 Intestinal Permeability Antigenic Screen is the most accurate intestinal barrier permeability test available and is currently the only lab that measures the immunological response against the intestinal barrier and accepted markers of permeability.  The profile includes actin/myosin network IgG, occludin/zonulin IgG, IgA, IgM and lipopolysaccharides (LPS) IgG, IgA, and IgM.  Measurements of these antibodies can be used as markers for intestinal permeability.  Elevations of occludin/zonulin antibodies indicate breakdown of the intestinal barrier integrity through paracellular (tight junction) pathways.  Elevations of actomyosin antibodies indicate breakdown of the intestinal barrier integrity through transcellular (across the intestinal cells) pathways and may also suggest possible autoimmunity against mucosal epithelium and other tissues that contain the actomyosin cytoskeleton.  Elevations of LPS antibodies indicate excess penetration of LPS into the bloodstream (leakiness).

doctor-without-answersConventional Management of Intestinal Permeability

There is currently no drug available to treat intestinal permeability and most doctors have not even heard of it.  However, this may change in the near future because drug companies are now working on drugs that modulate gut permeability.  There is currently a tight junction regulator being developed, intended for the treatment of patients with celiac disease which has just recently passed Phase IIb human drug trial development and will start Phase III clinical trials for the assessment of the oral drug’s efficacy and safety.[287]  Once this drug is approved, doctors, or at least gastroenterologists, will become more familiar with intestinal permeability.  However, at present, these drugs appear to be limited to approval for the treatment of this one particular intestinal autoimmune disorder (celiac disease).  So patients with intestinal permeability with diagnoses of other autoimmune conditions (or any other condition) will not be able to get drug treatments for the foreseeable future.

healing-leaky-gut-with-functional-medicineClinical Management of Intestinal Permeability in Functional Medicine

Fortunately, intestinal permeability usually responds very well to dietary and supplement intervention and can often be well-managed through these interventions alone.  The treatment of leaky gut should include an aggressive program designed to break the vicious cycle of leaky gut. This involves a restricted dietary regimen and nutritional supplements that have been shown to help healing-leaky-gut-with-foodreduce intestinal inflammation and help repair the intestinal lining. The dietary program may need to be conducted for an extended period of time for more progressed cases, depending on the factors involved in promoting leaky gut.  One of the things that will create variables for how long this will take are the mechanisms involved that are causing the leaky gut. If the person is still consuming alcohol or consuming inflammatory foods or has hormonal deficiencies or has blood sugar issues, this will take longer to correct. There will be some people that will have chronic leaky gut for the rest of their life, such as severe autoimmune conditions and people with systemic inflammatory conditions.

Intestinal Permeability Dietary Restrictions

As discussed above, it is important to avoid foods that tend to aggravate or worsen intestinal permeability when trying to repair the gut barrier and decrease autoimmune responses.  Sugars and high glycemic foods can create more damage to the intestinal lining and increase permeability.  Gluten (and other grains that cross-react with gluten), dairy and soy can also cause additional inflammation and lead to further damage to the epithelial lining of the GI tract.  Lectins (found in grains, legumes, nightshade plants and dairy) have also been shown to damage this epithelial ling.  It is important to implement an aggressive and complete dietary program to break the vicious cycle of leaky gut and minimize autoimmune reactions.   Here is a list of foods shown to aggravate or worsen intestinal permeability as well as the foods that are generally safely tolerated in individuals with this condition.

refined-carbsFoods to Avoid

  • Sugars: including corn syrup, high fructose corn syrup, molasses, honey, chocolate candy, etc.
  • High glycemic fruits: watermelon, mango, pineapple, raisins and canned fruit
  • Grains: including gluten, wheat, oats, rice, barley, buckwheat, soy, corn, wheat germ, spelt, amaranth, kamut, millet, and quinoa, etc.
  • Gluten-containing compounds: including processed salad dressings, ketchup, soy sauce, barbecue sauce, condiments, modified starches, etc.
  • dairyDairy: including milk, whey, eggs, cheeses, creams, and mayonnaise, etc.
  • Soy: including soy milk, soy sauce, soy protein, etc.
  • Alcohol: including beer, wine, sake, cognac, liquors, etc.
  • Lectins: including nuts, beans, soy, potatoes, tomato, eggplant, pepper, peanut oil, soy oil, etc.
  • Coffee
  • Processed foods
  • Canned foods

colorful-vegetablesFoods to Eat

  • Most vegetables (except tomato, potatoes and mushrooms): including asparagus, spinach, lettuce, broccoli, beets, cauliflower, carrots, celery artichokes, garlic, onions, zucchini, squash, rhubarb, cucumbers, turnips, watercress, etc.
  • Fermented foods: including sauerkraut, kimchi, pickled ginger, mixed pickle, coconut yogurt, kombucha tea, etc.
  • cooked-salmonMeats: including fish, chicken, beef, lamb, organ meats, etc.
  • Low glycemic foods: apricot, plum apple, peach, pear, cherries, berries, etc.
  • Coconut: including coconut oil, coconut bitter, coconut milk, etc.
  • Herbal teas
  • Olives and olive oil

best-supplements-for-leaky-gutNutritional Compounds Shown to Repair the Intestinal Lining

There are various plant compounds, vitamins and minerals that have been shown in the literature to have a restorative effect on a damaged intestinal barrier.  These include the following: L-glutamine  [288-292], deglycyrrhinized licorice [293-303], N-acetyl glucosamine [304-307], aloe leaf extract [308-312], spanish moss [313-317], marshmallow extract [318-321], methylsulfonylmethane (MSM) [322-325], gamma oryzanol [326-330], slippery elm bark [331-334], german chamomile [335-337], marigold flower extract [338-341], glutathione [342-347], zinc carnosine [348], vitamin D [349-351].

zinc-carnosine“Regarding intestinal permeability, zinc carnosine caused an approximate threefold increase in gut integrity and repair”[348]

“VDR (vitamin D receptor) plays a critical role in mucosal barrier homeostasis by preserving the integrity of junction complexes and the healing capacity of the colonic epithelium.  Therefore, vitamin D deficiency may compromise the mucosal barrier, leading to increased susceptibility to mucosal damage and increased risk of IBD (inflammatory bowel disease).”[349]

sunshine-in-hands“There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity” [350]

“1,25(OH)2D3 (vitamin D) may play a protective role in mucosal barrier homeostasis by maintaining the integrity of junction complexes and in healing capacity of the colon epithelium. 1,25(OH)2D3 may represent an attractive and novel therapeutic agent for the adjuvant therapy of IBD (inflammatory bowel disease).”[351]

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