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Zonulin (Stuhl): the pathway in the body

Zonulin (Stuhl) is part of the pathway “Zonulin and gut barrier”. This page shows the whole pathway; the station of Zonulin (Stuhl) is highlighted.

Where this laboratory value sits: Zonulin in stool — what test kits measure. Part of the released zonulin is found in stool and in blood. Studies show that widely used test kits do not capture pre-haptoglobin 2 itself, but related proteins such as properdin. Source 5

In brief

Zonulin is a protein that intestinal cells release to the outside after certain stimuli; it is the precursor of haptoglobin 2. From outside it binds receptors on those same cells and, through a signal inside the cell, loosens the junctions between them.

9 stations · 8 sources
ORYTriggers in the gutAction at the barrierMyD88Protein kinase Cactin scaffoldback to the cell surfaceStimulus at gut wallbacteria, gliadin fragmentsCXCR3 receptoron the intestinal cellZonulin is releasedinto the gut lumenZonulin in stoolwhat test kits measurePAR2 and EGFR receptorson the cell surfaceSignal inside the cellvia protein kinase CZO-1, occludin, claudinsjunction proteinsTight junction opensthe seam loosensPath between the cellsreversible state

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The pathway step by step

  1. Stimulus at gut wall → CXCR3 receptor Gliadin fragments bind to the CXCR3 receptor of the intestinal cell. The signal is passed inwards via the signalling protein MyD88. Source 1
  2. CXCR3 receptor → Zonulin is released · MyD88 In response, the cell releases zonulin to the outside. Zonulin is the precursor of the protein haptoglobin 2, which is why it is also called pre-haptoglobin 2. Source 2, 1
  3. Zonulin is released → Zonulin in stool Part of the released zonulin is found in stool and in blood. Studies show that widely used test kits do not capture pre-haptoglobin 2 itself, but related proteins such as properdin. Source 5
  4. PAR2 and EGFR receptors → Signal inside the cell Protein kinase C The receptor switches on protein kinase C. It attaches phosphate groups to the proteins of the junctions between two intestinal cells. Source 1
  5. Signal inside the cell → Tight junction opens · actin scaffold The junctions loosen and the actin scaffold contracts. As a result, the gap between two intestinal cells widens for a short time. Source 4, 1
  6. Tight junction opens → Path between the cells Water, ions and small molecules pass between the cells along this route. When the phosphate groups are removed again, the gap closes. Source 1, 3

Cofactors in this pathway

Sources

  1. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev 2011 · PubMed 21248165
  2. Tripathi A, Lammers KM, Goldblum S et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci U S A 2009 · PubMed 19805376
  3. Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 2016 · PubMed 28123927
  4. Zihni C, Mills C, Matter K et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 2016 · PubMed 27353478
  5. Scheffler L, Crane A, Heyne H et al. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. Front Endocrinol (Lausanne) 2018 · PubMed 29459849
  6. Newton AC. Protein kinase C: perfectly balanced. Crit Rev Biochem Mol Biol 2018 · PubMed 29513138
  7. Denker BM, Nigam SK. Molecular structure and assembly of the tight junction. Am J Physiol 1998 · PubMed 9458817
  8. Kabsch W, Holmes KC. The actin fold. FASEB J 1995 · PubMed 7781919

Whole pathway: Zonulin and gut barrier

Related pathways

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert approval pending
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