Zonulin and FABP2. Two blood serum markers to detect impaired intestinal barrier function.
What is a leaky gut?
A leaky gut means that the barrier function of the mucous membrane of the intestine is disturbed. As a result, bacteria and toxins from the gut can enter the bloodstream and promote systemic inflammation. In addition, disturbances occur in the absorption of nutrients, vitamins, trace elements, and enzymes secreted by the intestinal epithelium, such as lactase or diamine oxidase (DAO) which is important for the breakdown of histamine and are produced in reduced quantities. A leaky intestine is caused either by increased permeability of tight connections in the intestinal mucosa or by structural or functional damage to the intestinal epithelium itself.
Causes of leaky gut syndrome
Intestinal barrier disorder has been described for various intestinal diseases, but also systemic inflammatory diseases such as rheumatoid arthritis, migraines, autism, ADHD, depression, multiple sclerosis, or chronic fatigue syndrome (CFS). In addition to inflammatory bowel diseases, the pathogenesis of intestinal permeability disorder is often unclear. Bacterial colonization of the small intestine is often correlated, but it is very likely to be more a consequence than a cause. Many conditions can favor the appearance of a leaky gut, such as infections, intestinal exposure to toxic heavy metals, medications (NSAIDs, antibiotics, etc.), certain spicy foods, and alcohol consumption. Stress can also promote a leaky gut, possibly through alterations in the gut microbiome or stimulation of mast cells. Food intolerances and allergies can be both a cause and a consequence of a leaky gut.
Laboratory diagnostics of leaky gut
Leaky gut treatment is an important pillar in the treatment of chronic inflammatory diseases. Non-invasive laboratory markers are necessary for both diagnosis and treatment testing. The reference method is the carbohydrate challenge test and the determination of the lactulose/mannitol ratio. See: Leaky Gut Test. However, because this test requires effort and there is some strain on the patient, it is no longer used in practice.
Fatty acid binding protein 2 (FABP2)
FABP2 or otherwise intestinal fatty acid binding protein (I-FABP) is present in the cytoplasm of intestinal epithelial cells. It mediates the absorption of fatty acids. FABP2 is 100% gut specific. If the intestinal epithelium is damaged, FABP2 is released into the circulation and can be measured in serum. Numerous studies show that serum FABP2 level is a valid biomarker for intestinal permeability in celiac disease, wheat sensitivity, inflammatory bowel diseases, and depression, after extreme exercise, and is associated with clinical improvement after treatment.
Zonulin
An alternative blood marker for assessing leaky gut is zonulin, which belongs to the family of pro-haptoglobins. Microbes trigger the release of zonulin in the intestinal epithelium, which is why high zonulin levels are considered a marker for inflammatory leaky gut. However, with increasing inflammation and associated severe damage to the intestinal epithelium, the release of zonulin may decrease, and therefore an increase in zonulin caused by inflammation may not occur. This fact could explain the observation that different studies showed contradictory results for zonulin in terms of its association with gastrointestinal disorders.
FABP2 and zonulin levels may vary
FABP2 and zonulin are regulated differently. Zonulin is secreted by the epithelial cells of the small intestine. The prerequisites for this are (1) an inflammatory signal (inflammation) and (2) a minimal amount of intact intestinal epithelial cells that can produce zonulin. FABP2, on the other hand, is always present in sufficient quantities in the microvilli of intestinal epithelial cells. It is not controlled by inflammation but is released into the blood whenever there is structural damage to the intestinal epithelium.
When does FABP2 increase and when does zonulin increase?
The differences mentioned before, mean that zonulin is regulated mainly in the initial phase of inflammatory intestinal changes, while it can be normalized in the chronic phase. In the later (chronic) phase, FABP2 appears to have advantages in terms of sensitivity as a biomarker, as well as in all non-inflammatory intestinal epithelial lesions, e.g. in case of insufficient blood circulation due to stress, after antibiotic therapy or in case of damage with toxic heavy metals.
What do you need to measure in the laboratory?
One indicator is usually not enough. The results so far show that there is not always a correlation between the two blood markers. Although one indicator is enough to make a diagnosis, it is recommended to use both indicators. However, if (e.g. for cost reasons) it is decided to use only one indicator, then it is preferable to measure FABP2, as this is more reliable. However, if FABP2 is normal and there is evidence of a leaky gut, zonulin should also be measured.
Are there indicators of leaky gut in feces?
Alpha1-antitrypsin is a large protein (54 KDa) produced in the liver and passes into the feces only when the intestinal barrier is disturbed. Elevated fecal values indicate a relatively serious deficit in the intestinal barrier. In the case of milder intestinal barrier disorders, alpha1-antitrypsin is not sufficiently sensitive, possibly because it is broken down in the faeces by bacterial proteases depending on intestinal transit time. Fecal indicators sIgA and calprotectin are also widely used. However, these markers are used more as markers of inflammation, which is why they only marginally increase during ischemia, stress, or leakage states associated with toxic substances. If blood sampling is possible, the above-mentioned blood markers (FAPB2 and Serum Zonulin) should be preferred over the measurement of stool zonulin. Zonulin values fluctuate significantly depending on stool transit time and protease activity in faeces. FABP2 cannot be measured in faeces.
What are the sequelae phenomena associated with a leaky gut?
- Increase in food intolerances
Food intolerances are often the secondary result of chronic inflammatory processes in the intestine. The intestinal epithelium is the site of synthesis of enzymes such as diamine oxidase and lactase, which is why morphological changes in the intestinal mucosa caused by inflammation also lead to reduced synthesis of these enzymes. The determination of FABP2 and zonulin serves not only to diagnose leaky gut but also allows for monitoring of the course of treatment in secondary DAO deficiency (histamine intolerance) or secondary lactose intolerance.
- Absorption disorders
If the intestinal barrier is disturbed, food components, vitamins, and trace elements often cannot be adequately absorbed. The result is deficiency symptoms. Essential trace elements such as zinc, selenium, copper, magnesium, manganese, cobalt, and chromium play an important role as cofactors of many enzymes. Even a latent undersupply may, among other things, be associated with decreased cognitive performance or increased susceptibility to infections. In addition, certain minerals directly affect the intestinal barrier. Zinc interacts directly with tight junctions. In patients with elevated levels of FABP2 or zonulin, an adequate supply of minerals is therefore of great importance. To avoid overdose, administration should be based on the analysis of trace elements in the blood.
- Increased absorption of toxic metals
Toxic metals such as mercury, silver, tin, lead, arsenic, or aluminum enter the intestine both through release from dental fillings and through food. Normally, most of them are excreted again. When there is a leaky gut, on the other hand, there is increased absorption in the body and therefore toxic exposure.
