Zonulin: A Discovery that Changed the Way We View Inflammation, Autoimmune & Cancer

by Jill Carnahan, MD, ABFM, ABIHM, IFMCP

An amazing discovery made a few years ago revolutionized our ability to understand the gut and permeability and how gut health impacts a wide range of health conditions from cancer to autoimmune disease to inflammation and food sensitivities.


This Little Molecule, Zonulin, has Quite a Story…

Zonulin & Leaky Gut


Zonulin is the “Doorway” to Leaky Gut

Zonulin opens up the spaces between the cells of the intestinal lining, which normally occurs so that nutrients and other molecules to get in and out of the intestine. However, when leaky gut is present, the spaces between the cells open up too much, allowing larger protein molecules to get into the bloodstream where an immunologic reaction can take place. Once that happens, the body is primed to react to those proteins each and every time they appear. It can also cause leakage of intestinal contents, like bacteria into the immune system, creating inflammation and overloading the liver’s ability to filter out this garbage.


Triggers That Open the Zonulin Doorway

Based on Dr. Fasano’s research, we know that the two most powerful triggers to open the zonulin door are gluten and gut bacteria in the small intestine. Gliadin 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 that allow all sorts of things to pass right through.  This is called “leaky gut”. Its as if the security guard that keeps the bad guys out is taking a nap! Sometimes large food molecules will pass through to the immune system. The immune system thinks they are foreign invaders and will mount an immune response leading to food sensitivities. In addition, this immune activation leads to more damage of the intestinal cells (called enterocytes) and the gut becomes more inflamed and more permeable or “leaky”. As the damage continues, the microvilli that line the intestines and absorb nutrients become damaged, leading to other nutrient deficiencies.


Top Causes of Increased Zonulin & Development of Leaky Gut

  1. Overgrowth of harmful organisms, like bacteria or yeast in the intestine
    • SIBO = small intestinal bacterial overgrowth
    • Fungal dysbiosis or candida overgrowth
    • Parasite infections
  2. Gliadin in the diet (gluten containing foods)
Gliadin is a protein in wheat, that like gluten, is a trigger for people with celiac disease.

However, a study published in the Scandiavian Journal of Gastroenterology in 2006 clearly showed that gliadin can affect zonulin, even in people without the gene for celiac. The researchers concluded that:

Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

The significance of this is that gluten affects intestinal permeability in all persons, but to different extents. It also means that 100% of patients with autoimmune disease or leaky gut could potentially benefit from a gluten-free diet.


Elevated Zonulin Levels & Leaky Gut are Also Associated with the Following:

  1. Crohn’s disease
  2. Type 1 Diabetes
  3. Multiple Sclerosis
  4. Asthma
  5. Glioma
  6. Inflammatory Bowel Disease
In conclusion, the article states:

Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food-derived environmental triggers or changes in gut microbiota all seem to be key ingredients involved in the pathogenesis of inflammation, autoimmunity, and cancer. This new theory implies that [once this path is activated] it can be… reversed by preventing the continuous interplay between genes and the environment.

Original blog by Dr. Jill Carnahan can be found here.



About Jill Carnahan, MD, ABFM, ABIHM, IFMCP

Dr. Jill Carnahan emphasizes an integrative holistic approach to wellness using both conventional medicine and evidence-based complementary therapies, taking into account the whole person (body, mind, and spirit), including all aspects of lifestyle. She emphasizes the therapeutic relationship between physician and patient and seeks to give her patients a full range of healing options with an emphasis on healthy living, nutrition, and disease prevention.