Zonulin and Leaky Gut

Medical Theme Health and Care

An amazing discovery has dramatically altered our view of gut permeability and its impact on a wide range of conditions such as cancer, autoimmune disease, inflammation and food sensitivity.


Zonulin is a protein that moderates the permeability of tight junctions between cells of the wall of the digestive tract. It essentially opens up the spaces between the cells of the intestinal lining. This occurs normally so that nutrient molecules can get in and out of the intestine. In leaky gut, these intercellular spaces open up too much allowing larger protein molecules to enter the bloodstream. Once in the bloodstream these proteins can elicit an immune response. After this occurs, the body is primed to react to these proteins every time they enter the bloodstream. Intestinal contents, bacteria can also leak in creating inflammation.

Zonulin Triggers:

The two most powerful triggers are gluten and gut bacteria in the small intestine. Gliadin (a class of proteins present in wheat and several other cereals within the grass genus Triticum) causes zonulin levels to increase both in those people who have celiac disease and those who do not. As the zonulin level rises, the seal between the intestinal cells diminishes, opening up spaces between cells. This is called “leaky gut”. The immune system views these particles in the bloodstream as foreign invaders and will subsequently mount an immune response. This can lead to food sensitivities. Furthermore, this immune activation can damage the intestinal cells and the gut becomes more permeable and more inflamed. Over time the microvilli that line the intestines become damaged. The villi seen in a healthy gut lining are almost completely lost in celiac patients, greatly reducing the surface area and impairing nutrient absorption.

Top Causes of Increased Zonulin and Development of Leaky Gut:

Overgrowth of harmful organisms, like bacteria or yeast in the intestine
• SIBO = small intestinal bacterial overgrowth
• Fungal dysbiosis or candida overgrowth
• Parasite infections
• Gliadin in the diet (gluten containing foods)

A study published in the Scandinavian Journal of Gastroenterology in 2006 clearly showed that gliadin can affect zonulin even in people without the gene for celiac. Based their results, it was concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.
Elevated Zonulin Levels And Leaky Gut Are Also Associated With The Following:
Inflammatory Bowel Disease

• Crohn’s disease
• Type 1 Diabetes
• Multiple Sclerosis
• Asthma

Miscommunication between innate and adaptive immunity, exposure to environmental triggers, genetic predisposition, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food and environmental triggers all seem to be key in the pathogenesis of inflammation and autoimmunity.
How to check your zonulin levels:

There are a couple of ways to check your zonulin levels. The first is a simple blood test to check for levels of protein expression in the blood.
A second option is the lactulose or mannitol test, which assesses the gut permeability by measuring the levels of both compounds in urine after they have been ingested. The patient drinks a premeasured amount of lactulose and mannitol. The degree of intestinal permeability or malabsorption is reflected in the levels of the two sugars recovered in a urine sample collected over the next 6 hours.

So to summarize, zonulin is an important modulator of gut permeability. It has strong associations with several disorders of the gut. This protein was first described in the 2000s and is therefore very new. Genetic markers, diagnostic tests are still being developed.

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