Leaky Gut Syndrome: Definition and Diagnosis
Content
1. What is leaky gut?
1.1 Structure of the intestinal barrier
1.1.1 Zonulin & permeability
1.2 Symptoms of leaky gut
2. Diagnostic approaches for leaky gut
2.1 Sugar Test
2.2 Zonulin
2.3 Endoscopy with biopsy
2.4 Alpha-1-Antitrypsin
2.5 I-FABP
3. Summary
1. What is leaky gut?
Leaky gut syndrome describes a condition in which the intestinal lining becomes more permeable (increased intestinal permeability). This is often associated with immune activation and a disrupted microbiome.
1.1 Structure of the intestinal barrier
The gastrointestinal tract (digestive tract) is, along with the skin and respiratory tract, one of the body’s largest contact surfaces with the external environment. The intestinal barrier has an important function: it must not only separate the body from the outside world and protect it from invading pathogens or harmful substances (barrier function) but also allow the absorption of essential nutrients. These contradictory requirements necessitate a certain degree of permeability while maintaining a tight seal.
1.1.1 Zonulin & permeability
Permeability refers to the ability of the intestine to allow substances to pass through. The intestinal lining consists of a single layer of cells (enterocytes), which are connected by “tight junctions.” The number of tight junctions is regulated by factors such as zonulin. Zonulin is released by the intestinal mucosa and can be measured in both blood and stool. Elevated levels are a marker for increased intestinal permeability (“leaky gut”). A disrupted intestinal barrier allows larger molecules, toxins, and bacteria to enter the bloodstream, which can activate the immune system and trigger inflammatory responses.
1.2 Symptoms of leaky gut
Common symptoms of leaky gut syndrome include digestive issues such as diarrhea, constipation, bloating, gas formation, abdominal pain and discomfort, fatigue, headaches, muscle pain, concentration difficulties (“brain fog”), skin problems such as acne, eczema, and rosacea, as well as joint pain and systemic inflammation. Associated conditions include psychological symptoms such as depression and anxiety, chronic fatigue, autoimmune diseases (e.g., rheumatoid arthritis, psoriasis), and diabetes (1). Since the 1970s, leaky gut syndrome has been linked to intestinal inflammation, chronic inflammatory bowel diseases, celiac disease, and NSAID-induced ulcers.
2. Diagnostic approaches for leaky gut
As of November 2024, leaky gut syndrome is not recognized as an independent disease, and no standard diagnostic test exists. However, several tests can indicate increased intestinal permeability, including the sugar test, zonulin, alpha-1-antitrypsin, I-FABP (intestinal fatty acid-binding protein), and biopsies.
2.1 Sugar Test
The sugar test, also known as the lactulose-mannitol test, is a well-established method for measuring intestinal permeability. The patient drinks a solution containing these two sugar molecules. Mannitol is easily absorbed, whereas lactulose is larger and typically absorbed only in small amounts.
The urine is collected over several hours (typically 5–6) and analyzed for the concentration of both sugars. In a healthy individual, more mannitol than lactulose is expected in the urine. About 10 to 30% of ingested mannitol should be recovered in the urine, while only about 1% of lactulose should be detected (2).
A healthy balance indicates normal intestinal permeability. Deviations may indicate issues: an increased lactulose-to-mannitol ratio suggests increased intestinal permeability, while low levels of both sugars may indicate general intestinal damage. This test has been considered the gold standard since the 1970s and is commonly used to investigate the role of intestinal permeability in various diseases.
2.2 Zonulin
Zonulin is a protein that plays a key role in regulating intestinal permeability. It affects the tight junctions—cellular “seals” in the intestinal mucosa—and can loosen them, increasing permeability.
Zonulin can be measured in both blood and stool. Elevated zonulin levels are considered a biomarker for an increased risk of leaky gut. In diagnostics, zonulin measurement is a non-invasive and relatively cost-effective method that provides insights into intestinal barrier function.
Studies suggest that increased zonulin levels may be associated with chronic conditions such as celiac disease, type 1 diabetes, and inflammatory bowel diseases. However, the interpretation and significance of these values remain controversial. Some studies show that serum zonulin levels do not strongly correlate with the sugar test (3,4), and stool-based zonulin measurements also show limitations compared to the sugar test, which remains the gold standard (5).
Nevertheless, testing for zonulin levels is a useful starting point for diagnosing leaky gut (5).
2. 3 Endoscopy with biopsy
Endoscopy with biopsy collection provides a direct way to assess intestinal health and identify signs of a damaged intestinal barrier. A tissue sample from the intestinal mucosa is taken and examined microscopically. This method can reveal structural changes in the intestinal barrier, such as damaged tight junctions or inflammatory processes.
For chronic intestinal diseases like celiac disease, Crohn’s disease, or ulcerative colitis, biopsy is considered the gold standard for evaluating the intestinal mucosa. Although this method is precise, it is invasive and is typically only used in severe or unclear cases when non-invasive tests like the sugar test or zonulin measurement do not yield conclusive results.
2.4 Alpha-1-Antitrypsin
Alpha-1-antitrypsin is mainly produced in the liver and has the task of regulating inflammatory processes. Alpha-1-antitrypsin is also considered an inflammatory marker for the intestinal mucosa in a stool examination. Elevated levels of alpha-1-antitrypsin indicate a loss of the protein via the intestinal wall into the intestine and thus an increased permeability of the intestine.
Especially in inflammatory bowel diseases such as Crohn’s disease or ulcerative colitis, the levels of alpha-1-antitrypsin in the stool can be elevated due to increased immune reactions.
As a non-invasive diagnostic tool, alpha-1-antitrypsin measurement in stool is often used in combination with other tests to assess the function of the intestinal barrier and identify systemic and local inflammatory processes.
2.5 I-FABP
Intestinal fatty acid-binding protein (I-FABP) is found in the cytoplasm of intestinal epithelial cells and helps absorb fatty acids from the intestinal lumen. When intestinal cells are damaged, I-FABP is released into the bloodstream. Elevated serum I-FABP levels may indicate acute intestinal damage, epithelial disruption, and increased permeability of the intestinal wall.
Diseases such as Crohn’s disease, celiac disease, or severe infections can make I-FABP a valuable diagnostic marker. Although highly specific for the intestine, I-FABP is often used in combination with other biomarkers for a more comprehensive assessment of gut health.
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3. Zusammenfassung
The exact definition and diagnosis of leaky gut require further research (as of 2024). However, the listed diagnostic tools can provide an initial assessment of whether increased intestinal permeability may contribute to certain symptoms and complaints. A thorough evaluation of test results should be conducted by an experienced physician in conjunction with additional diagnostic methods, such as gut microbiome analysis.
References
- Leech B, McIntyre E, Steel A, Sibbritt D. Risk factors associated with intestinal permeability in an adult population: A systematic review. Int J Clin Pract. 2019 Oct;73(10):e13385. doi: 10.1111/ijcp.13385. Epub 2019 Jul 5. PMID: 31243854.
- https://my.kresserinstitute.com/wp-content/uploads/2020/10/FM-Gut-Diagnosis-Intestinal-Permeability-Assessment-Interpretation-Guide-Clinician-Handout.pdf; zuletzt geprüft 14.11.2024>/li>
- Tatucu-Babet OA, Forsyth A, Owen E, Navarro-Perez D, Radcliffe J, Benheim D, Mendis H, Jois M, Itsiopoulos C, Tierney AC. Serum zonulin measured by enzyme-linked immunosorbent assay may not be a reliable marker of small intestinal permeability in healthy adults. Nutr Res. 2020 Jun;78:82-92. doi: 10.1016/j.nutres.2020.05.003. Epub 2020 May 19. PMID: 32563954.
- Massier L, Chakaroun R, Kovacs P, Heiker JT. Blurring the picture in leaky gut research: how shortcomings of zonulin as a biomarker mislead the field of intestinal permeability. Gut. 2021 Sep;70(9):1801-1802. doi: 10.1136/gutjnl-2020-323026. Epub 2020 Oct 9. PMID: 33037053; PMCID: PMC8355880.
- Wegh CAM, de Roos NM, Hovenier R, Meijerink J, Besseling-van der Vaart I, van Hemert S, Witteman BJM. Intestinal Permeability Measured by Urinary Sucrose Excretion Correlates with Serum Zonulin and Faecal Calprotectin Concentrations in UC Patients in Remission. J Nutr Metab. 2019 Apr 1;2019:2472754. doi: 10.1155/2019/2472754. PMID: 31061734; PMCID: PMC6466955.
