You may or may not have heard of zonulin. Since its discovery in 2000 by researcher Alessio Fasano, it has become associated with the condition leaky gut.
We always take an evidence-based approach and in this article we discuss why zonulin is released, what effects if has on the body and how it has now been linked to a myriad of health concerns including diabetes, obesity and autoimmune conditions.
What is zonulin?
Zonulin is a small protein that is produced by the epithelial cells in the gut – it is sometimes referred to as the gate keeper for the intestinal lining.
The gastrointestinal tract not only functions to enable the digestion of food and absorption of nutrients, it also plays a vital role in defence against invasion.
The cells of the gut lining are specialised and allow absorption of nutrients whilst at the same time preventing undigested food particles, bacteria and toxins from entering the blood stream.
A normal gut lining comprises healthy cells tightly squeezed up against each other, creating a natural physical barrier.
Zonulin is known to open up the spaces between the cells in the intestinal lining (1).
It plays a key role in promoting a healthy immune system and works with immune tissues and cells in the gut to maintain a healthy tolerance to substances.
Dysregulation of zonulin pathways leads to an increase in the gaps between the cells in the intestinal lining.
Opening up of the gut lining leads to increased intestinal permeability, also called leaky gut.
This allows large particles, bacteria and toxins to enter the blood stream, which provokes an immune response and can lead to many different symptoms, including inflammation.
Leaky gut and autoimmune conditions
Once the immune system is exposed to foreign particles, be that food or pathogens, the natural response is to release chemical messengers (called cytokines) which increase inflammation.
As the immune system does not recognise the foreign particles, antibodies are produced.
A food particle that has passed through the leaky gut can lead to development of food sensitivities.
Although the immune system is highly sophisticated and complex, it doesn’t always get it right.
As part of the process of recognising a particle as an invader, the immune system sends out markers – after a period of time of being bombarded with foreign particles (via a leaky gut), the immune system can mistakenly mark body tissues that look very similar to the invading molecules and begin to attack them.
This is thought to be involved in many autoimmune conditions such as rheumatoid arthritis (2), Crohn’s and thyroid issues like Hashimoto’s and Grave’s.
The researcher who discovered zonulin believes that, as it regulates intestinal barrier function, it is the biological door to autoimmune disease and inflammation (3).
What causes increased zonulin?
Many factors may be involved in triggering the release of zonulin. By far the most significant are small intestinal exposure to bacteria and gliadin from gluten containing grains (3, 4).
The link between gluten consumption and disruption to the intestinal barrier in coeliac disease has been extensively studied.
Coeliac disease has a known genetic factor and it seems that this, along with the presence of gluten in the diet, can cause an over expression of zonulin – leading to increased intestinal permeability and damage to the gut lining.
The effect gluten has on the gut lining is not just confined to those with coeliac disease, studies indicate most people experience a degree of increased intestinal permeability after eating gluten containing grains (5).
Imbalances to the microbiome, the complex ecosystem that resides in the gut, can affect the gut lining and zonulin release.
Situations such as Small Intestinal Bacterial Overgrowth (SIBO) where there are excess levels of bacteria not normally seen in the small intestine, fungal dysbiosis like candida, and parasite infestations may all contribute.
In addition, chronic stress (6), heavy metals and toxins, and poor dietary choices may also affect the health of the gut lining.
Zonulin and chronic health conditions
Aside from the significant impact on the development of autoimmune conditions, zonulin overexpression has also been linked to many other health conditions.
- Gut health
With its direct link to gut structure and health, it may come as no surprise to hear that zonulin can be seen to be elevated in cases of inflammatory bowel disease.
Those with Crohn’s and ulcerative colitis both show increases in zonulin and intestinal permeability (7).
Zonulin is also upregulated in IBS – both the constipating type and the type that results in diarrhoea – and levels of zonulin seen may be comparable to levels seen in coeliac disease (8).
- Metabolic health
Research into zonulin and metabolic health is giving very interesting results.
Type 1 diabetes is an autoimmune condition that shares some genetic associations with coeliac disease.
Research into zonulin levels in Type 1 diabetes show that levels can be increased in almost half of those with the condition.
What’s more, researchers discovered that zonulin upregulation can begin in the pre-diabetic stage before the condition becomes established (9).
Gestational diabetes has also been linked to intestinal permeability and other factors that are involved include obesity and insulin resistance.
A small observational study in 2017 showed that zonulin measured in early pregnancy may be increased (10).
A further study conducted in 2019 indicated that zonulin may be used as a predictor for the onset of gestational diabetes alongside other factors such as obesity (10).
A study into the dietary intake and gut health of overweight pregnant women was assessed alongside zonulin levels and showed that women with a lower zonulin level had more diversity of species of bacteria in the gut as well as increased fibre, omega-3 and a range of vitamins and minerals in their diet (11).
This indicates that nutritional intake and balancing gut bacteria may aid in reducing zonulin levels in women more susceptible to the development of gestational diabetes.
Another condition strongly linked with insulin resistance, poor blood sugar control and inflammation is polycystic ovary syndrome (PCOS).
A case controlled study on women with a recent diagnosis of PCOS, and healthy controls, showed zonulin is increased in women with PCOS and correlates with insulin resistance and severity of menstrual disorders.
The authors suggest that intestinal permeability may play a role in the development of PCOS (12).
Obesity is now known to be a chronic inflammatory condition and the presence of insulin resistance is common.
Levels of zonulin are known to be increased in obesity and seem to increase in line with measurements such as BMI and waist to hip ratio (13).
These results suggest that increased intestinal permeability in obesity may be associated with the development of metabolic conditions such as Type 2 diabetes (14).
These findings were backed up by a more recent study which found that increased zonulin levels were associated with a higher waist circumference, fasting glucose, cholesterol, diastolic blood pressure and an increased risk of metabolic disease and obesity.
Interestingly they found no association with zonulin levels and those reporting gastrointestinal symptoms or gastrointestinal disease (15).
Childhood obesity is on the rise and is a major cause for concern as the onset of Type 2 diabetes in childhood is also rising.
A 2017 study highlighted that zonulin may be increased in children with obesity (16).
This leads us to question what impact will this have on the development of chronic inflammatory conditions and autoimmune diseases in adulthood?
- Nervous system
There are indications that zonulin may exert more widespread effects and a 2018 study showed that not only are the cells in the gut affected by zonulin but also those that make up the blood-brain barrier (BBB).
The authors of the in vitro study comment that breakdown of the BBB plays an important role in the development of neurological diseases such as stroke, epilepsy and multiple sclerosis and that the effects of zonulin may explain the involvement of the communication between the gut and the brain in central nervous system diseases (17).
One study into the link between the gut and mental health disorders, such as anxiety and depression, found that dysbiosis, the imbalance of the bacteria in the gut, was linked to an increase in zonulin and increased intestinal permeability, even in individuals who reported no signs of gastrointestinal problems (18).
The link between the gut and autism spectrum disorders (ASD) and ADHD has been discussed for many decades.
There is much debate around the link with gluten and ASD and whether there is impaired intestinal integrity or not.
Recent studies have shown that zonulin levels were higher in patients with ASD compared to healthy controls and that the higher levels were associated with a higher childhood autism rating (19).
Disruptions to the gut brain axis (the communication between the gut and the brain) have been seen in conditions such as ADHD.
Researchers have found that higher zonulin levels were linked to more impairment in social functioning and could be used as an independent predictor of hyperactivity (20).
What can you do to control zonulin?
Zonulin has been found to be a reversible marker.
Managing the two most common stimuli for triggering zonulin release is a good place to start.
Avoiding gluten containing grains may have a significant impact for some people. It is advisable when going ‘gluten-free’ to avoid replacing the gluten containing products with commercially available alternatives as these are generally lower in nutrient content and heavily processed.
Test results can be used by your practitioner to develop a Personalised Health programme designed to restore your gut to optimal health.
Choosing more healthful foods such as fresh fruits and vegetables, good fibres, oily fish and lean organic grass fed poultry and meat versus highly processed foods rich in fat, sugar and salt is beneficial.
Addressing toxicity and opting to detoxify through juicing, smoothies or raw foods may also help.
In the busy modern world, long term stress management is key.
Chronic stress plays a role in many health issues and, in order to keep a healthy gut and mind, activities such as mindfulness, meditation, yoga and Tai chi may aid in reducing stress levels.
Therapies such as CBT or NLP can help with thought patterns and reactions around stress.
Preserving the integrity of natural barriers such as the gut lining and the blood-brain barrier help to protect the body and prevent against the development of chronic diseases.
If you would like further information on how an Amchara Personalised Health practitioner may help with your symptoms, please get in touch.
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