In this article, we will take a deep dive into a common marker found on comprehensive stool tests, Zonulin. We look at what zonulin is, it's association to health issues, what it means for your gut health and what can influence zonulin levels. We also explore natural treatments to help lower your faecal zonulin levels.
Zonulin is a protein that helps regulate how easily substances can pass through the walls of our intestines. It controls the openings and closings of the tight connections between cells in the intestinal lining. A scientist named Alessio Fasano (1) discovered zonulin in 2000, which started the discussion about "leaky gut" and how it may contribute to inflammatory problems not only in the gut but also in other parts of the body (1,2).
When we eat, have an imbalance of bacteria in our gut, experience stress, or activate our immune system, certain cells in the gut can release zonulin. Zonulin then starts a series of processes that cause the tight connections between intestinal cells to open up. Some foods, like gluten (specifically a component called gliadin), have been found to stimulate zonulin more than others. So, if zonulin levels are found to be high, it may be recommended to remove gluten from the diet to help reduce its stimulation (3,4).
Zonulin measured in stool – what’s considered ‘normal’ range would be 100 µg/g and elevated zonulin would be anything over > 100 µg/g, however, clinically, a marker over 20/30ug/g should be taken into context with other markers such as calprotectin, occult blood etc, to make an appropriate assessment of your client’s gastrointestinal health picture. We should also be mindful that stool zonulin levels may also be influenced by the transit time of stool through the gut, as zonulin may be degraded or absorbed before being excreted.
Zonulin in blood – this is used far less commonly in clinic; however, optimal range is said to be <38ng/ml. It should be noted that zonulin levels in the blood can fluctuate quite significantly, therefore a singular reading may not be reliable (5).
Our intestinal barrier acts as a gateway for substances entering our bodies. Until a substance crosses this barrier, it is technically considered to be "outside" of the body. That's why there is a lot of immune activity happening at this point. This immune activity, along with the gut microbiome (the community of microorganisms in our gut), helps the immune system determine what it needs to respond to, such as pathogens, chemicals, toxins, and what it doesn't need to respond to, such as the foods we eat and our own cells (2).
When levels of zonulin are high, our tolerance for certain substances decreases and inflammation increases. This combination of inflammation and increased intestinal permeability leads to the production and movement of pro-inflammatory molecules called cytokines, which has been linked to various diseases. Conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), multiple sclerosis (MS), rheumatoid arthritis, type-1 diabetes, asthma, lupus, autism spectrum disorders (ASD), as well as Alzheimer's, Parkinson's, and dementia, have been associated with leaky gut and elevated levels of zonulin (6,7,8).
This emphasizes the importance of markers like zonulin in identifying and addressing issues with the intestinal barrier early on. By monitoring zonulin levels, we can potentially detect and manage problems with intestinal permeability, which may help in preventing or managing certain diseases.
Sleep deprivation has been shown to increase the production of zonulin in the gut, which may lead to increased intestinal permeability or "leaky gut." Several studies have linked sleep deprivation with increased zonulin levels and increased intestinal permeability in both animals and humans (9,10,11) One study found that after just one night of sleep deprivation, healthy individuals had significantly increased levels of zonulin in their blood compared to when they had a full night's sleep (9).
Specifical studies looking at the relationship between stress and zonulin production look at stress induced by public speaking, which induced an increase in zonulin levels in the blood of the participants (12).
The exact mechanism by which stress affects zonulin production is not fully understood. However, it is believed that stress hormones, such as cortisol, may play a role. Cortisol is known to affect the permeability of the gut barrier and may increase the production of zonulin in the gut (13).
Overall, stress can disrupt the normal regulation of zonulin in the gut, leading to increased intestinal permeability and potentially contributing to a range of health problems. Managing stress through techniques such as meditation, exercise, and counselling may help reduce the negative effects of stress on gut health (12,13).
Functional stool tests that we use routinely in clinic, either include zonulin as standard or as an add on. Identifying your zonulin status can help to assess whether there is evidence of intestinal permeability and begin to work on improving this critical area of your health. A result above 100ng/g is typically significant, however, a lower figure may also require further support depending on other gut health markers such as calprotectin and occult blood as well as the clinical symptoms someone is presenting with
As part of our Health Score assessment, which you can take for free in our Health Hub, one of the sections looks at the most common signs of intestinal permeability. If you score moderate or high risk in that section, as well as other gastrointestinal or chronic inflammation sections, you may find it extremely beneficial to run a comprehensive stool test.
- Zinc L-carnosine: Zinc L-carnosine has been shown to have antioxidant and anti-inflammatory effects on the mucosa of the gut. It is commonly used for upper gastrointestinal health issues such as peptic ulcers, H-pylori and GERD; however, it has also shown promise with colitis (17).
- L-glutamine: Glutamine has shown to significantly reduce zonulin levels, which has led to a decline in intestinal permeability (15).
- Probiotics: Certain probiotic strains, such as Lactobacillus and Bifidobacterium, have been shown to reduce zonulin levels and improve gut barrier function (19).
- Omega-3 fatty acids: Omega-3 fatty acids have anti-inflammatory properties and have been shown to improve gut barrier function, thus reducing zonulin levels (18).
- Additional nutritional substances such as bovine colostrum, pectin derived from apples, and vitamins A and D have been discovered to regulate the epithelial barrier by decreasing zonulin levels in the bloodstream (19).
- Stress management: Chronic stress can increase zonulin levels and contribute to leaky gut. Stress management techniques such as meditation, deep breathing, and yoga can help reduce stress and improve gut health (12,13).
- Sleep hygiene: As discussed above, sleep plays a key role in the health of your gut and zonulin production. Ensuring your room is as dark as possible, do not watch TV too late, don’t have your phone plugged in by your bed. Having a bath or shower prior to bed is a good way of lowering your body temperature and thus having a better night sleep (9,10,11).
- Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016 Oct 21;4(4). doi:10.1080/21688370.2016.1251384
- Fasano A. Intestinal permeability and its regulation by zonulin: Diagnostic and therapeutic implications. Clinical Gastroenterology and Hepatology. 2012 Aug 16;10(10):1096–100. doi:10.1016/j.cgh.2012.08.012
- Takiishi T, Fenero CI, Câmara NO. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers. 2017 Sept 28;5(4). doi:10.1080/21688370.2017.1373208
- Barbaro MR, Cremon C, Morselli-Labate AM, Di Sabatino A, Giuffrida P, Corazza GR, et al. Serum zonulin and its diagnostic performance in non-coeliac gluten sensitivity. Gut. 2020 Feb 14;69(11):1966–74. doi:10.1136/gutjnl-2019-319281
- Vojdani A, Vojdani E, Kharrazian D. Fluctuation of zonulin levels in blood vs stability of antibodies. World Journal of Gastroenterology. 2017 Aug 21;23(31):5669. doi:10.3748/wjg.v23.i31.5669
- Hu X, Wang T, Jin F. Alzheimer’s disease and gut microbiota. Science China Life Sciences. 2016 Aug 26;59(10):1006–23. doi:10.1007/s11427-016-5083-9
- Stadlbauer V, Engertsberger L, Komarova I, Feldbacher N, Leber B, Pichler G, et al. Dysbiosis, gut barrier dysfunction and inflammation in dementia: A pilot study. BMC Geriatrics. 2020 Jul 20;20(1). doi:10.1186/s12877-020-01644-2
- An J, Liu Y, Wang Y, Fan R, Hu X, Zhang F, et al. The role of intestinal mucosal barrier in autoimmune disease: A potential target. Frontiers in Immunology. 2022 Jul 1;13. doi:10.3389/fimmu.2022.871713
- Wang Z, Chen W-H, Li S-X, He Z-M, Zhu W-L, Ji Y-B, et al. Gut microbiota modulates the inflammatory response and cognitive impairment induced by sleep deprivation. Molecular Psychiatry. 2021 May 7;26(11):6277–92. doi:10.1038/s41380-021-01113-1
- Barceló A, Esquinas C, Robles J, Piérola J, De la Peña M, Aguilar I, et al. Gut epithelial barrier markers in patients with obstructive sleep apnea. Sleep Medicine. 2016 Oct 27;26:12–5. doi:10.1016/j.sleep.2016.01.019
- Tian Y, Yang W, Chen G, Men C, Gu Y, Song X, et al. An important link between the gut microbiota and the circadian rhythm: Imply for treatments of circadian rhythm sleep disorder. Food Science and Biotechnology. 2022 Jan 18;31(2):155–64. doi:10.1007/s10068-021-01015-6
- Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2013 Oct 23;63(8):1293–9. doi:10.1136/gutjnl-2013-305690
- Linninge C, Jönsson P, Bolinsson H, Önning G, Eriksson J, Johansson G, et al. Effects of acute stress provocation on cortisol levels, zonulin and inflammatory markers in low- and high-stressed men. Biological Psychology. 2018 Aug 15;138:48–55. doi:10.1016/j.biopsycho.2018.08.013
- Chen Q, Chen O, Martins IM, Hou H, Zhao X, Blumberg JB, et al. Collagen peptides ameliorate intestinal epithelial barrier dysfunction in immunostimulatory Caco-2 cell monolayers via enhancing tight junctions. Food & Function. 2017 Mar 22;8(3):1144–51. doi:10.1039/c6fo01347c
- Shariatpanahi ZV, Eslamian G, Ardehali SH, Baghestani A-R. Effects of early enteral glutamine supplementation on intestinal permeability in critically ill patients. Indian Journal of Critical Care Medicine. 2019 Aug 23;23(8):356–62. doi:10.5005/jp-journals-10071-23218
- Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: A double-blind, randomized trial. Gastroenterology. 2003 Jun;124(7):1792–801. doi:10.1016/s0016-5085(03)00323-8
- Efthymakis K, Neri M. The role of zinc L-Carnosine in the prevention and treatment of gastrointestinal mucosal disease in humans: A review. Clinics and Research in Hepatology and Gastroenterology. 2022 Jun 2;46(7):101954. doi:10.1016/j.clinre.2022.101954
- Durkin LA, Childs CE, Calder PC. Omega-3 polyunsaturated fatty acids and the intestinal epithelium—a review. Foods. 2021 Jan 19;10(1):199. doi:10.3390/foods10010199
- RAMEZANI AHMADI A, SADEGHIAN M, ALIPOUR M, AHMADI TAHERI S, RAHMANI S, ABBASNEZHAD A. The effects of probiotic/synbiotic on serum level of zonulin as a biomarker of intestinal permeability: A systematic review and meta-analysis. Iranian Journal of Public Health. 2020 Jul 6; doi:10.18502/ijph.v49i7.3575
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The above article was contributed by
Benjamin
Primary Author
