Fatty Acid-Binding Protein 2 (FABP2), also known as intestinal fatty acid-binding protein (I-FABP), is a protein that plays a crucial role in the transport of fatty acids in the small intestine. It is a member of the fatty acid-binding protein family, which includes several related proteins with similar functions in various tissues. FABP2 has been studied as a potential biomarker for various gastrointestinal diseases. Elevated levels of FABP2 in the blood indicate intestinal mucosal damage, making it a marker for conditions like celiac disease, Crohn's disease, and other gastrointestinal disorders.
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FABP2 is a small cytosolic protein with a molecular weight of approximately 15 kDa. It consists of 127 amino acids and has a beta-barrel structure, forming a hydrophobic cavity that can bind and transport hydrophobic fatty acids. While FABP2 is primarily found in the small intestine, it is also expressed in the liver and other tissues to a lesser extent.
FABP2's main function is to bind to long-chain fatty acids and transport them across the enterocyte (the absorptive cells of the small intestine). It facilitates the absorption of dietary fatty acids, which are essential for energy production and various physiological processes. FABP2 is involved in lipid metabolism and plays a role in regulating lipid uptake and storage in the small intestine.
What is a leaky gut?
A leaky gut means that the barrier function of the mucous membrane of the small intestine is disturbed. As a result, bacteria and toxins from the intestine can enter the bloodstream and promote systemic inflammation. Furthermore, there are disturbances in the absorption of nutrients, vitamins, and trace elements, and enzymes secreted by the intestinal epithelium, such as histamine-degrading diamine oxidase, are produced to a reduced extent. Leaky gut is caused by either increased permeability of the tight junctions in the intestinal mucosa or structural or functional damage to the intestinal epithelia themselves.
Causes of leaky gut syndrome
A disturbed intestinal barrier has been described for intestinal diseases, but also other systemic inflammatory diseases such as rheumatoid arthritis, migraines, autism, ADHD, depression, multiple sclerosis, or chronic fatigue syndrome (CFS). Apart from inflammatory bowel disease, the pathogenesis of intestinal permeability disorder is often unclear. The gut microbiome as well as the immune system, particularly mechanisms of impaired tolerance, are often associated with a leaky gut. Numerous circumstances can promote leaky gut, such as food intolerances, intestinal exposure to toxic metals, infections, medications (NSAIDs, antibiotics, etc.), spicy foods, and alcohol consumption. Stress can also lead to a leaky gut, possibly through psychosomatic changes in the microbiome or through sympathetic stimulation of mast cells.
Laboratory diagnostic evidence of leaky gut
The treatment of leaky gut is an important pillar in the therapy of chronic inflammatory diseases. Non-invasive laboratory markers are essential for both diagnosis and therapy control.
The reference method is the lactulose/mannitol quotient, which is rarely carried out due to the effort and strain on the patient, but which non-invasive laboratory markers must be measured against. In this test, the patient takes a lactulose/mannitol mixture orally. As a small molecule, the monosaccharide mannitol is absorbed transepithelial in a relatively unlimited manner, while the larger disaccharide lactulose only enters the blood through the open tight junctions in leaky gut paraepithelial areas. An increased intake of lactulose (measured as the lactulose/mannitol ratio in the urine after 2-6 hours) indicates a disturbed intestinal barrier function.
The stool markers alpha 1-antitrypsin, sIgA, and calprotectin are often leaky gut markers. Strictly speaking, the latter two represent inflammatory markers, which is why they do not increase or hardly increase during ischemia, stress, or toxic-related leaky conditions. Alpha 1-Antitrypsin is a large protein (54 KD) produced in the liver that only passes into the stool when the intestinal barrier is disturbed. Elevated levels in stool indicate a severe intestinal barrier deficiency. In the case of milder barrier defects, alpha1-antitrypsin is not sufficiently sensitive, probably because it is broken down by bacterial proteases in the stool.
The intestinal fatty acid binding protein FABP2 currently appears to be the most suitable marker for a disturbed intestinal barrier. FABP2 occurs exclusively in the cytoplasm of intestinal epithelial cells (100% specific) and plays a role in fatty acid metabolism. If the intestinal epithelium is damaged, FABP2 is released into the circulation and can be measured in the serum.
Numerous studies show that the I-FABP serum level is a biomarker for intestinal permeability and correlates with both morphologically detectable epithelial damage and the reference method, the lactulose/mannitol ratio.
Patients with active celiac disease have elevated serum FABP2 levels. The level correlates with the severity of villous atrophy and the level of transglutaminase IgA antibodies and increases with gluten consumption. FABP2 therefore also serves as a compliance marker in the individual course.
In non-celiac wheat sensitivity (NCWS), increased FABP2 levels can be measured, which normalizes with diet. FABP2 correlates significantly with LBP (lipopolysaccharide-binding protein) and soluble CD14 (sCD14), a nonspecific marker of monocyte activation, in the NCWS cohort. sCD14 therefore does not reflect impaired intestinal permeability, but rather systemic inflammation. The parallel increase in FABP2, sCD14, and LBP in NCWS supports the connection between leaky gut and systemic inflammation because of the translocation of microbial antigens from the intestine.
Elevated levels of I-FABP in serum are also found in mesenteric infarction and necrotizing colitis.
In patients with depression, FABP2 is significantly elevated and correlates with symptom severity. This underlines the already-known association of increased intestinal permeability with depressive symptoms.
The FABP2 serum level increases significantly with 60 minutes of vigorous exercise on a bicycle ergometer and correlates with intestinal hypoperfusion. This observation shows that FABP2 is released not only when enterocytes are destroyed, but also when intestinal permeability increases due to the changes associated with physical stress (such as increased body temperature, oxidative stress, compression of intestinal motility, and reduced visceral blood flow).
FABP2 is a very stable protein, which is why it is a reliable laboratory parameter. Since FABP2 is always actively eliminated in the organism via the kidneys promptly, a currently measured value in the serum always reflects the daily release.
Zonulin
A marker in the blood (and stool) that has often been used as an indicator of leaky gut is zonulin, a protein secreted by enterocytes that regulates the opening of tight junctions. Bacteria such as E. coli or Salmonella typhi and, in at least some patients, gliadin triggers the release of zonulin and thereby opens the tight junctions. Therefore, measurably high zonulin levels are considered a marker for inflammatory leaky gut. However, if there is severe damage to the intestinal epithelium, an inflammation-triggered increase in zonulin may not occur due to the disturbed (reduced) zonulin production in damaged enterocytes. In HIV patients, low zonulin levels are associated with increased mortality, which is explained by the fact that intestinal epithelial function is drastically impaired in these patients. In patients with depression, plasma zonulin was even reduced despite increased FABP2.
The fact that only morphologically and functionally intact enterocytes secrete zonulin could not only be responsible for the unexpectedly low values in seriously ill patients but also for the fact that different studies show contradictory results regarding the correlation with gastrointestinal complaints.
It appears that measurement of FABP2, rather than zonulin, is preferable for the diagnosis of leaky gut.
FABP2 Gene Polymorphism
Genetic variations in the FABP2 gene have been associated with differences in fat absorption and metabolism. Certain FABP2 gene polymorphisms may increase the risk of obesity and related metabolic conditions.
