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 400 m2. (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, including the signs and symptoms, what causes leaky gut, risk factors, associated health conditions, as well as an overview of the four Rs, a therapeutic approach to healing leaky gut.
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, including atopic diseases and inflammatory bowel disease (IBD). (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)
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:
- Cognitive issues, such as memory problems or brain fog
- Digestive issues, such as chronic diarrhea or constipation
- Joint pain
- Multiple food sensitivities
- Nutrient malabsorption and resulting deficiencies
- Skin conditions, such as acne vulgaris (1)(2)(3)(4)(5)(12)(14)(15)
Causes and risk factors
Several factors may affect gut health and contribute to increased intestinal permeability, including:
- Antibiotic use
- Certain medications (e.g., NSAIDs, immunosuppressants)
- Chronic or excessive stress
- Excessive alcohol consumption
- Exposure to environmental toxins
- Gluten, a protein found in certain grains (e.g., wheat, barley, rye)
- Infections (e.g., viral infections)
- Nutrient deficiencies (e.g., vitamin A, vitamin D)
- Poor diet (e.g., low fiber, excessive carbohydrate and saturated fat)
- Poor gut health or bacterial imbalance (2)(9)(13)(16)(20)
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)
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)
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)
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)
How to heal leaky gut: 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)
Download a handout on the 4Rs of gut healing.
The bottom line
Leaky gut syndrome occurs when the lining of the intestinal tract becomes compromised, allowing substances into the blood and lymph, such as toxins, microorganisms, and antigens. When left unaddressed, leaky gut syndrome can negatively affect overall health and lead to chronic inflammatory conditions. If you’re a patient, consult your integrative healthcare practitioner, who can recommend leaky gut syndrome diet modifications, specific testing, and a personalized leaky gut treatment plan.
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- Arrieta, M. C., Bistritz, L., & Meddings, J. B. (2006). Alterations in intestinal permeability. Gut, 55(10), 1512–1520.
- Bischoff, S. C., Barbara, G., Buurman, W., Ockhuizen, T., Schulzke, J. D., Serino, M., … Wells, J. M. (2014). Intestinal permeability– A new target for disease prevention and therapy. BMC Gastroenterology, 14, 189.
- Bowe, W. P., & Logan, A. C. (2011). Acne vulgaris, probiotics and the gut-brain-skin axis – back to the future? Gut Pathogens, 3(1), 1.
- Caulfield, L., McCormick, B., Murray-Kolb, L., Lee, G., Schulze, K., Ross, A. C., … Kosek, M. (2019). Intestinal permeability and inflammation mediate dietary intake associated risks of micronutrient deficiencies at 15 months: Results from the MAL-ED study (OR07-04-19). Current Developments in Nutrition, 3(Suppl 1).
- Dai, Y. J., Wang, H. Y., Wang, X. J., Kaye, A. D., & Sun, Y. H. (2017). Potential beneficial effects of probiotics on human migraine headache: A literature review. Pain Physician, 20(2), E251-E255.
- Fasano A. (2012). Intestinal permeability and its regulation by zonulin: Diagnostic and therapeutic implications. Clinical Gastroenterology and Hepatology, 10(10), 1096–1100.
- Fasano A. (2012). Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences, 1258(1), 25–33.
- Gecse, K., Róka, R., Séra, T., Rosztóczy, A., Annaházi, A., Izbéki, F., … Wittmann, T. (2012). Leaky gut in patients with diarrhea-predominant irritable bowel syndrome and inactive ulcerative colitis. Digestion, 85(1), 40–46.
- 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.
- Krawczyk, M., Maciejewska, D., Ryterska, K., Czerwińka-Rogowska, M., Jamioł-Milc, D., Skonieczna-Żydecka, K., … Stachowska, E. (2018). Gut permeability might be improved by dietary fiber in individuals with nonalcoholic fatty liver disease (NAFLD) undergoing weight reduction. Nutrients, 10(11), 1793.
- 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.
- Morris, G., Berk, M., Carvalho, A., Caso, J., Sanz, Y., & Maes, M. (2016). The role of microbiota and intestinal permeability in the pathophysiology of autoimmune and neuroimmune processes with an emphasis on inflammatory bowel disease type 1 diabetes and chronic fatigue syndrome. Current Pharmaceutical Design, 22(40).
- Mu, Q., Kirby, J., Reilly, C. M., & Luo, X. M. (2017). Leaky gut as a danger signal for autoimmune diseases. Frontiers in Immunology, 8.
- Obrenovich M. (2018). Leaky gut, leaky brain? Microorganisms, 6(4), 107.
- Odenwald, M., & Turner, J. (2016). The intestinal epithelial barrier: A therapeutic target? Nature Reviews Gastroenterology & Hepatology, 14(1).
- 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).
- Smyth, M. C. (2017). Intestinal permeability and autoimmune diseases. Bioscience Horizons, 10.
- 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.
- 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.
- Travis, S., & Menzies, I. (1992). Intestinal permeability: Functional assessment and significance. Clinical Science, 82(5), 471–488.