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Zonulin is a protein found in humans that acts as the “gatekeeper” of the intestinal wall. It is currently the only known human protein that can naturally and reversibly open the tight junctions between the cells of your digestive tract.
How it was Discovered:
Interestingly, zonulin was discovered while researchers were studying Cholera. They found that the cholera bacteria produce a toxin called Zonula occludens toxin (Zot) that makes people sick by forcing the gut gates open. They eventually realised that the human body makes its own version of this toxin to regulate itself—and they named it Zonulin.
To understand zonulin, it helps to think of your gut lining as a high-security wall with millions of tiny gates. Zonulin is the signal that tells those gates to open or close.
1. Its Main Role: Controlling “Leaky Gut”
– The primary function of zonulin is to regulate intestinal permeability.
– When Closed (Low Zonulin): Your intestinal cells are packed tightly together. Only water and tiny nutrients can pass through into the bloodstream. This keeps out bacteria, toxins, and undigested food.
When Open (High Zonulin): Zonulin signals the “tight junctions” to disassemble. The gaps between cells grow larger, allowing bigger molecules to “leak” into the bloodstream. This is the physiological basis of what is commonly called Leaky Gut Syndrome.
2. Why Does the Body Have This Signal?
It might seem strange that the body has a built-in mechanism to make the gut “leaky,” but it serves a protective purpose:
– Flushing Out Pathogens: If you ingest harmful bacteria, the gut releases zonulin to open the gates. This allows water to flow into the intestine (causing diarrhoea) to flush the bacteria out and allows immune cells to move into the gut to fight the infection.
– Nutrient Transport: It helps regulate the absorption of certain larger molecules and fluids during the digestive process.
3. What Triggers Zonulin Release?
In a healthy person, zonulin is released in small, controlled bursts. However, two main triggers can cause it to be released excessively:
1. Bacteria (Dysbiosis): When harmful bacteria or an overgrowth of bacteria (like SIBO) colonise the small intestine, the body releases zonulin as a defense mechanism.
2. Gliadin (Gluten): As we discussed previously, gliadin is a major trigger. In many people—especially those with Celiac Disease or gluten sensitivity—gliadin binds to receptors in the gut and triggers a massive release of zonulin.

4. Zonulin and Disease
When zonulin levels remain high for too long, the “gates” stay open, leading to chronic inflammation. This has been linked to several conditions:
– Celiac Disease: Where the response to gluten and zonulin is most severe.
– Type 1 Diabetes: Research by Dr. Alessio Fasano (the discoverer of zonulin) found that increased zonulin often precedes the development of T1D.
– Autoimmune Disorders: Such as Multiple Sclerosis and Rheumatoid Arthritis, as the “leaked” particles can trigger systemic immune attacks.
- “Leaky Brain”: Recent studies suggest zonulin can also affect the Blood-Brain Barrier, potentially linking gut health to neurological issues like “brain fog” or anxiety.