Zonulin, the protein that makes us waterproof over the years

In search of more years and more life, we start this 2022 at the search for a bookmark what would be behind of most of the most frequent diseases. Just as chronic inflammation is a common factor in all of them, a protein called zonulin may be telling us that something is wrong.

Just a year ago, we opened 2021 with an article in which we reviewed the key elements for health, according to a scientific review by the professor Carlos Lopez-Otín, entitled ‘The Hallmarks of Health’, which we could translate as ‘Lthe hallmarks of health ‘.

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Precisely the first element referred to by López-Otín is the integrity of the protective barriers in the body. These have a double function, regulating traffic between body compartments and avoiding the passage of external agents. And we gave the example of the alterations of the intestinal permeability, and that we also associated dysbiosis or imbalance in the microbiota, the populations of microorganisms that reside in our intestines and that regulate our metabolism in an amazing way. It is a subject that we deal with in depth with the Dra. Silvia Gómez Senent.

But the alterations in the permeability of the barriers in the body go beyond the intestinal one, probably the best known. Another barrier of great importance is the hematoencefálica, that regulates the passage of substances to the brain very precisely. In fact, drugs whose objective is to have activity in the central nervous system must be designed in such a way that their chemical structure allows them to cross this barrier. Hyperpermeability of the blood-brain barrier has been associated with neurodegenerative diseases.

A sieve like a tennis court

One of the most studied membranes in the organism is the intestinal wall. This very fine barrier composed of a single layer of cells (the enterocytes) has a function that we could equate to that of a cotton sieve. Let’s imagine we filter a mixture of substances through this sieve. Part of them will pass through the filter through the holes that exist in the mesh of the fabric, and others will do so by soaking the cotton fibers, being able to ‘drip’ from the other side.

It is an intuitive way of explaining the two processes by which substances can cross the intestinal barrier: paracellular permeability (between cells), which would be the case of passing through the holes in the sieve, or transcellular permeability (through cells), where the substance enters the interior of the enterocyte and is transported to the other side of the membrane, into our body.

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The passage of substances through this intestinal membrane is highly regulated, since it fulfills multiple functions: allow the passage of nutrients, water and ions, but not of toxins or other substances. In addition, the intestine also has immune function and the development of tolerance to food antigens.

Can we measure intestinal permeability to know if it is altered? Tests have been developed in which the subject is given a known quantity of two different sugars and their excretion through urine. Lactitol is absorbed preferably paracellularly, and mannitol transcellularly. If there is a higher than normal amount in the urine of any of them, we can have an idea that intestinal permeability it is altered and enlarged.

This is indicative that undesirable substances, such as certain bacterial toxins named lipopolisacáridos. These substances are highly toxic, and minute amounts can trigger symptoms. In fact, they are responsible for the serious consequences of septic shock from a generalized infection, which can even lead to death.

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With intestinal hyperpermeability, there is the constant and continuous passage of small amounts of these toxins. This triggers what is called endotoxemia: a chronic low-level intoxication, which continuously activates the immune system and chronic inflammatory processes. That Chronic inflamation, which as we explained here is the silent killer, is the common factor in diseases such as cardiovascular, metabolic or neurodegenerative.

Therefore, the state of that ‘sieve’ that we have in the intestine is of great importance, since if it has holes or is ‘frayed’ substances will be passing into the body, with undesirable effects. Let us also bear in mind that, if we spread the entire surface of our intestine on a flat surface, it would occupy approximately the size of a tennis court. A large area open to everything we eat.

Zonulina, the guardian of the barrier

As the mechanisms that regulate intestinal permeability have been studied, some ‘pores’ have been discovered between the enterocytes that make up the intestinal wall, called intimate unions or tight unions. The passage through these pores is highly regulated, by a set of different proteins. Among others, are the occludins, claudins and the best known and probably studied, the zonulinas.

Measuring zonulin levels in the blood, it has been possible to analyze the relationship between its increase or decrease, and the presence of different diseases. Furthermore, the observation that increased intestinal hyperpermeability was associated with worse prognosis in many of these pathologies.

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An example would be autoimmune diseases. The model that would explain this type of disease comprises, on the one hand, the genetic predisposition, and on the other, environmental factors, since not all individuals with this predisposition develop the disease. And that environmental factor can be substances that, in situations of intestinal hyperpermeability, cross the barrier and slip into our body, triggering autoimmunity.

Thus, in the Diabetes type 1 It has been observed that zonulin levels are elevated with respect to individuals who do not suffer from the disease. In addition, in samples prior to the development of the disease, elevated levels of zonulin could be observed in 70% of the patients who after 3.5 years on average began to develop symptoms. In this way, we would find a marker that can have predictive value. Similar results have been found for other autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis or psoriasis, among other.

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The intestinal wall is not the only membrane regulated by zonulin in our body. We have already pointed out that another of the very important barriers is the blood-brain, which controls traffic to and from the brain. Its regulation has been studied in relation to neurodegenerative diseases, such as the Alzheimer’s, Parkinson’s or nerve conditions related to multiple sclerosis.

In multiple sclerosis patients, zonulin levels are elevated relative to healthy controls and they are associated with the prognosis of the disease at one year. In addition, a parallelism is observed between the levels of zonulin and the disturbances of the blood-brain barrier. In relation to Parkinson’s, zonulin has been measured, as well as markers of intestinal inflammation such as calprotectin, finding higher levels in patients than in healthy controls.

Zonulin and longevity

As we have verified, alterations in zonulin levels are related to inflammatory and neurodegenerative diseases. But what about longevity? To our knowledge, there is only one study that analyzes this question, prepared by a team led by the Spanish researcher Alexander Lucia, and in which the difference was verified in zonulin levels among centenariansyoung, healthy controls and patients with early heart attack.

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The results are enlightening: centenarians had lower levels of zonulin and of circulating bacterial toxins than young patients with early infarction. Furthermore, toxin levels in centenarians were even lower than in healthy young patients. It is only a preliminary study, but one that demonstrates the link between zonulin, intestinal permeability, chronic inflammation, and myocardial infarction. A causal chain that is increasingly confirmed with greater firmness.

What can we do?

Beyond genetic predisposition, which may also be associated with zonulin levels and better regulation from intestinal permeability or other barriers, habits have a lot to say. Agents like coffee, alcohol or certain food additives, in addition to a poor diet in general, can increase intestinal permeability. Also, when the microbiota is alteredA very high-fat diet can increase the absorption of bacterial toxins.

I personally find very useful in my clinical practice both the analysis of intestinal hyperpermeability with the lactitol-mannitol test like the measurement of zonulin levels and the analysis of the microbiota and intestinal parasites. The objective is to establish a series of measures to improve intestinal health, and in many cases I observe that they are associated with clinical improvement in diseases where inflammation plays an important role, or with the improvement of other health markers such as blood lipids. or glycemic control.

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