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Understanding Leaky Gut Syndrome

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Dr. Alex Keller, ND

The intestinal lining, made up of a single layer of specialized epithelial cells, facilitates absorption of nutrients while acting as a barrier to potentially harmful substances passing through the digestive tract, such as toxins, microorganisms, and other antigens. In humans, the surface area of epithelial cells that line the intestines can measure up to 400m2. (13) When exposed to certain environmental triggers, the epithelium can be adversely affected, resulting in a condition known as Intestinal Hyperpermeability or Leaky Gut Syndrome

This article provides an overview of leaky gut syndrome, signs and symptoms, causes and risk factors, associated health conditions, as well as an overview of the four Rs, a therapeutic approach to healing leaky gut.

A young woman cooking in a kitchen with an assortment of colorful vegetables.

An approach to treating leaky gut called the four Rs includes dietary and lifestyle modifications.

What is leaky gut syndrome?

Increased intestinal permeability, also referred to as leaky gut syndrome by integrative healthcare practitioners, (15) is an intestinal condition characterized by alterations to the tight junction (TJ) protein complexes of the intestinal epithelial cells. (2)

The intestinal barrier is made up of a single layer of epithelial cells separated by tight junctions, which acts as the primary physical barrier separating the lumen (space inside the intestine) from the gut submucosa. (6) Under normal conditions, tight junctions in the intestinal lining are selectively permeable, facilitating the absorption of certain substances, including nutrients, water, and electrolytes obtained through the digestive process. While the intestinal lining permits entry of these substances, it provides a protective barrier, preventing the absorption of potentially harmful molecules into the body, such as toxins, pathogens, and other antigens. (16)

Several factors may affect gut health and contribute to increased intestinal permeability

Explaining the mechanisms behind leaky gut

Gut microbiota modifications, damage to the epithelial cells of the intestines, and alterations to the mucus layer can all lead to increased intestinal permeability, leading to the increased and potentially harmful transfer of contents from the lumen to the inner layers of the intestinal wall. (2)

With altered levels of intestinal permeability, substances such as drugs, amino acids, (14) toxins, microorganisms, and other antibody generating (antigen) substances from the lumen can penetrate through the epithelial lining and be circulated by the blood and lymphatic system. (13) When in the blood, these substances can lead to immune activation and systemic low-grade inflammation. (12) As a result, loss of intestinal barrier function can occur gradually and lead to chronic inflammatory conditions. (2)

The presence of pathogens in the gut results in the secretion of pro-inflammatory substances known as cytokines, (12) which may increase epithelial cell shedding. When cell shedding occurs, the remaining gap between cells can be too large for the tight junctions to seal. This is one proposed mechanism that affects the intestinal barrier and increases intestinal permeability. (2)

Young family walking through a park in early autumn.

Many of the factors that contribute to leaky gut can be controlled, such as dietary triggers, stress management, and excessive alcohol consumption.

Contributing factors

Zonulin is a protein secreted by the intestinal tract that is associated with increased intestinal permeability. Environmental triggers, such as bacteria and the gliadin (gluten) protein, may stimulate the release of zonulin from the lamina propria, a layer of connective tissue below the intestinal epithelium. While zonulin has been shown to down-regulate the tight junctions between epithelial cells, this process is reversible and normally resolved by removing the environmental triggers. (1)(6)

Further, an imbalance of gut microbiota, known as dysbiosis, may play a role in the development of leaky gut. The microorganisms of the digestive tract are a part of the physical barrier, protecting against colonization by opportunistic bacteria, and regulating the absorption of nutrients to provide energy for the epithelial cells of the gut. Environmental factors, such as chronic alcohol consumption, a low-fiber diet, and overconsumption of saturated fat, have been associated with modifications to the bacterial balance and increased intestinal permeability. (13)

Signs and symptoms

Several signs and symptoms have been associated with leaky gut syndrome, including:

  • Multiple food sensitivities (2)
  • Digestive issues, such as chronic diarrhea or constipation (15)
  • Nutrient malabsorption and resulting deficiencies (4)
  • Skin conditions, such as acne vulgaris (3)
  • Cognitive issues, such as memory problems or brain fog (14)
  • Fatigue (12)
  • Headaches (5)
  • Joint pain (1)

Causes and risk factors

Several factors may affect gut health and contribute to increased intestinal permeability, including:

  • Antibiotic use 
  • Exposure to environmental toxins 
  • Nutrient deficiencies (e.g., vitamin A, vitamin D)
  • Infections (e.g., viral infections)
  • Poor gut health or bacterial imbalance (2)
  • Gluten, a protein found in certain grains (e.g., wheat, barley, rye) (9)
  • Certain medications (e.g., NSAIDs, immunosuppressants) (20)
  • Excessive alcohol consumption (13)
  • Poor diet (e.g., low fiber, excessive carbohydrate and saturated fat) (2)(13)
  • Chronic or excessive stress (13)(16)

Systemic symptoms of leaky gut may include headaches, joint pain, and cognitive issues.

Related health conditions

Research suggests that increased intestinal permeability may be associated with a number of health conditions, including irritable bowel syndrome, inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis), celiac disease, chronic inflammatory conditions (e.g., rheumatoid arthritis), obesity, and type 1 diabetes. 

Irritable bowel syndrome 

Irritable bowel syndrome (IBS) is a group of functional disorders that affect the digestive system. Increased intestinal permeability can be seen in individuals with IBS following acute infectious gastroenteritis. (14) Research has also found that clinical symptoms, including stool frequency, are correlated to levels of intestinal permeability in the colon of patients with diarrhea-predominant IBS (IBS-D). (8)

Inflammatory bowel diseases 

Ulcerative colitis (UC) and Crohn’s disease are characterized as inflammatory bowel diseases (IBD). Increased small intestine permeability has been found in individuals with a high risk of developing Crohn’s disease. (14) On the other hand, increased large intestine permeability was found in inactive UC patients, meaning the period between flare-ups of the disease. (8) Experimental studies suggest that preserving tight junction function in the intestinal barrier may help delay the progression of UC. (15)

Sliced fresh bread and bread knife on a rustic cutting board

Gluten, a protein found in certain grains such as wheat, barley, and rye, has been shown to increase intestinal permeability.

Celiac disease

There is a positive correlation between intestinal permeability and celiac disease (CD), (15) an autoimmune condition triggered by the consumption of gluten-containing grains in genetically-susceptible individuals. Exposure to gluten in the diet leads to damage of the mucosa in the small intestine. In celiac disease, altered intestinal permeability and structure of tight junctions results in reduced gut barrier function. (16)

Rheumatoid arthritis

Human data suggests that intestinal permeability is increased in rheumatic diseases, such as rheumatoid arthritis. (15) The connection between rheumatoid arthritis (RA) and leaky gut may be associated with microbiome health, as studies suggest that patients with RA have decreased gut microbial diversity compared to healthy controls. (18)

Obesity and metabolic syndrome

Intestinal hyperpermeability in obese patients has been associated with symptoms of metabolic syndrome, inflammation, and non-alcoholic fatty liver disease. Researchers suggest that an association between altered gut barrier function and hyperglycemia (elevated blood glucose) may be responsible for the inflammatory effects of the metabolic syndrome, a group of conditions that include high blood pressure, increased abdominal fat, and elevated cholesterol levels. Elevated levels of zonulin were also found to be associated with factors involved in obesity and metabolic syndrome, such as waist to hip ratio, fasting insulin, body mass index, and interleukin-6 (IL-6), a marker of immune activation. (6)

Type 1 diabetes

It has been suggested that alterations in the tight junctions of the epithelium may be involved in the development of type 1 diabetes (T1D). (7) T1D is a disorder characterized by an autoimmune response against the body’s beta cells (β cells) of the pancreas, leading to insufficient insulin production and hyperglycemia. Research in humans has found impaired intestinal barrier function to be present before the onset of T1D. (13)

Homemade beef bone broth in a bowl

Anti-inflammatory foods that support digestive health include vegetables, fruit, bone broth, and wild-caught fish.

The four Rs

A therapeutic approach known as the four Rs is commonly used to treat leaky gut syndrome. This approach involves the following steps:

Remove, where pathogens and inflammatory triggers are removed (11) (e.g., gluten-free diet, the elimination diet)

Replace, where essential nutrients that support digestive health are added to the diet (e.g., anti-inflammatory foods, high-fiber foods, prebiotics) (10)

Reinoculate, where beneficial bacteria are introduced through probiotic supplements or fermented foods (13)

Repair, where certain nutrients are used to help promote healing of the gut (e.g., l-glutamine, zinc) (11)

Further considerations

The pathophysiology of leaky gut syndrome is complex, and researchers are uncertain whether leaky gut is a contributor to or a result of various disorders. (1)(15) Testing for intestinal permeability includes oral lactulose and mannitol sugar probes (19) and plasma or urinary testing of sucrose. (2) Zonulin is also used a biomarker for leaky gut in autoimmune, tumoral, and neurodegenerative diseases. (7)

For further information or to discuss a potential diagnosis of intestinal permeability. we recommend working with your integrative healthcare provider, who can recommend specific testing and provide you with a personalized treatment plan.

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    9. Guerreiro, C. S., Calado, Â., Sousa, J., & Fonseca, J. E. (2018). Diet, microbiota, and gut permeability-The unknown triad in rheumatoid arthritis. Frontiers in Medicine, 5, 349.
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    11. Maes, M. & Leunis, J. C. (2008). Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: Effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuroendocrinology Letters, 29(6), 902-10.
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    16. Sander, G. R., Cummins, A. G., & Powell, B. C. (2005). Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Letters, 579(21).
    17. Smyth, M. C. (2017). Intestinal permeability and autoimmune diseases. Bioscience Horizons, 10.
    18. Sturniolo, G. C., Leo, V. D., Ferronato, A., D’Odorico, A., & D’Incà, R. (2001). Zinc supplementation tightens “leaky gut” in crohn’s disease. Inflammatory Bowel Diseases, 7(2), 94–98.
    19. Teixeira, T. F., Collado, M. C., Ferreira, C. L., Bressan, J., & Peluzio, M. (2012). Potential mechanisms for the emerging link between obesity and increased intestinal permeability. Nutrition Research, 32(9), 637–647.
    20. Travis, S., & Menzies, I. (1992). Intestinal permeability: Functional assessment and significance. Clinical Science, 82(5), 471–488.

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