Zonulin Family Peptide

Optimal Result: 22.3 - 161.1 ng/mL.

Zonulin is a biomarker and regulator of gastrointestinal tight gap junctions. 

Research and clinical studies of the protein zonulin and the zonulin signaling pathway demonstrate the clinical efficacy of zonulin as a biomarker of intestinal permeability. Studies also confirm that zonulin signaling is an essential mechanism in promoting healthy immune function and tolerance at the gastrointestinal mucosal barrier. 

Dysregulation of the zonulin signaling pathway disrupts normal gut barrier function and alters immune responses. As a result, high levels of zonulin may point to the presence of increased intestinal permeability. Over time, persistent high levels of zonulin in the blood may predispose susceptible individuals to inflammatory, autoimmune, and even neoplastic disorders by increasing the paracellular permeability of the gastrointestinal mucosa. As increased intestinal permeability persists only in the presence of high zonulin levels, the biomarker may also be used to monitor therapeutic interventions designed to restore gut barrier function. Zonulin is the only currently known reversible regulator of intestinal permeability. 

What is zonulin? 

The paracellular tight junctions between the intestinal epithelial cells are a critical component of the mucosal barrier and regulate the functional state of the paracellular pathway. Zonulin is a protein that regulates the reversible permeability of tight junctions. Zonulin is the endogenously produced analog of the Vibrio cholerae enterotoxin Zot. When Zot or zonulin bind to intestinal epithelial cells, a signal cascade is induced. The signal cascade disassembles the paracellular tight junctions between the epithelial cells of the intestinal mucosa, which increases intestinal permeability. However, the effects of Zot and zonulin are reversible. The tight junctions are the most apical structures to the gut lumen and are the rate-limiting factor for the paracellular migration of molecules through the intestinal barrier. In the small intestine, epithelial cohesion is maintained by the apical junction complex, composed of tight and zonula adherens junctions. The gastrointestinal mucosa forms a barrier between the body and the contents of the gut lumen. The mucosal barrier regulates the passage of macromolecular compounds through the intestinal epithelium to the gut-associated lymphoid tissue. The competence of the paracellular pathway is regulated by the zonulin signaling pathway, the gut-associated lymphoid tissue (GALT) and neuroendocrine networks. The dendritic cells of the GALT are found in the lamina propria layer of the gut mucosa. The dendritic cells take up antigens, process them and load them onto human leukocyte antigen (HLA) proteins for presentation to T-cells. The antigens presented may promote tolerant/ anti-inflammatory or proinflammatory T-cell induction. 

Zonulin is a pre-haptoglobulin (pre-HP2), and levels are modulated by the presence or absence of haptoglobin (HP) gene. Zonulin release in the small intestine occurs when a chemokine receptor is stimulated by gliadin or chemokines and induces proinflammatory signaling pathways in gastrointestinal epithelial cells. The released single-chain zonulin activates the cell-signaling pathway via epidermal protease-activated receptor 2 and growth factor. This results in disassembly of the tight paracellular junctions between the gut epithelial cells. When zonulin is cleaved by either complement component 1 (C1RL) in the cellular endoplasmic reticulum or by intestinal tryptase IV, it is converted into hapto-globlulin, a protein with heme (iron)-binding, antioxidant and antimicrobial properties. Haptoglobin does not affect tight junctions. 

Zonulin levels may increase due to inflammation, infection, injury, diet, or disease, altering the tight junctions between the epithelial cells and allowing increased passage of macromolecular proteins, toxins, and microorganisms into systemic circulation. Loss of tight junction functions and increased intestinal permeability may alter the delicate balance of tolerance and immune response essential to health and trigger inflammatory T-cell responses. Simple sugars, sodium, emulsifiers, the food additive microbial transglutaminase, and nanoparticles may disrupt intestinal barrier function and increase zonulin levels. In susceptible individuals, inflammatory disease or autoimmunity may develop. 

The connection between gluten and zonulin: 

Zonulin release has been triggered experimentally by the presence of gluten-derived gliadin in the gut lumen. The production of specific gliadin-derived peptides by digestive enzymes activates protease activated receptor 2 (PAR2) and epidermal growth factor (EGFR) and protease activated receptor 2 (PAR2). This signal cascade promotes disassembly of small intestine tight junctions. The loss of tight junctions allows gliadin and other antigens to enter the lamina propria layer of the small intestine where they are presented to the enteric immune cells, inducing a shift in immune function. The shift to proinflammatory signaling results in an increased peripheral immune response to gliadin. Dendritic cells loaded with gliadin antigen can migrate from the small intestine to the mesenteric and pancreatic lymph nodes, promoting inflammatory responses in the small intestine or pancreas. 

Implementation of a gluten-free diet may prevent further activation of the zonulin pathway and the autoimmune process, however, the loss of barrier function may persist for years in cases of gastrointestinal autoimmunity such as celiac disease. The composition of the gastrointestinal microbiome, including the resident gut microbes, is frequently altered in individuals with celiac disease and other autoimmune disorders, which may promote proinflammatory signaling and enhance the translocation of gliadin into the intestinal villi. 

Zonulin and bacterial adhesion: 

The epithelial surface of the gut mucosa is covered by a thick mucus layer. The microbiome of resident gastrointestinal bacteria and lipopolysaccharides from bacterial cell walls induce the secretion of mucus from host goblet cells. The mucus layer is protective—it prevents the direct adhesion of gastrointestinal bacteria to the epithelium, has a high concentration of secretory IgA, and provides binding sites for resident microbes. In the small intestine, the mucus layer covers both the villi and the villi tips. Disruption of the mucus layer from altered immunity, poor diet, or other causes, or alterations in resident microbes and gut ecology, may contribute to proinflammatory signaling and increased bacterial adhesion to the mucosa. The penetrability of the inner mucus layer, which normally repels bacteria, is determined at least in part by the immune system. The direct adhesion of pathogen or resident bacteria to the wall of the small intestine stimulates the release of zonulin from the gut mucosa and increases intestinal permeability. 

Association of elevated zonulin with increased gut permeability and autoimmune conditions:

Autoimmune disorders result from genetic predisposition, environmental exposures, and gut dysbiosis caused by altered populations of resident gut microbiota. The induction of an autoimmune response requires effector T-cells to acquire specific cytokine “fingerprints” and then migrate to target organs where they promote tissue inflammation. Increased intestinal permeability alters immune functions and increases antigen passage through paracellular channels. Animal studies indicate that epithelial barrier dysfunction may be a causative factor in autoimmune disorders. In fact, studies in IBD animal models have shown that increased intestinal permeability occurs early in pathogenesis and precedes the development of symptomatic disease. 

High levels of zonulin are found in the tissues and fluids of autoimmune patients. Elevated serum levels of zonulin and increased intestinal permeability are commonly observed in patients at risk of developing disease long before the onset of symptoms (e.g. Type 1 diabetes). 

Several autoimmune, inflammatory and neoplastic diseases have been associated with elevated levels of zonulin: 

Celiac disease—In those with the genetic predisposition (HLA-DQ2/8) and exposure to gluten, increased zonulin levels open the tight junctions and intestinal damage occurs. The breach of the intestinal barrier promotes proinflammatory T-cell signaling. Zonulin levels increase during the acute phase of the disease and decrease after gluten is removed from the diet and healing occurs. In celiac patients, serum zonulin has been correlated with lactulose/mannitol permeability testing.

Non-celiac gluten sensitivity (NCGS)—A 2015 study demonstrated that individuals with NCGS have zonulin levels higher than a normal control population, but lower than values for those with celiac disease.

Inflammatory bowel disease (IBD)—In children with IBD, elevated zonulin levels were associated with the presence of atopic symptoms. None of the IBD patients in the study were diagnosed with celiac disease. Interleukin-10 knockout mice, which develop chronic, patchy colitis and increased intestinal permeability, do not develop symptoms if treated with a zonulin inhibitor from weaning. Germ-free animals are also protected from symptoms, which implies trigger factors arise from the gut lumen.

Diarrhea-predominant irritable bowel syndrome (IBS-D)—A 2015 study demonstrated that individuals with IBS-D have zonulin levels that are higher than a normal control population, but lower than values for those with celiac disease. Increased transit times in this population are associated with HLA-DQ2/8 genotype.

Type 1 diabetes (T1D)—The autoimmune cause of pancreatic β-cell destruction has yet to be elucidated. However, 40% of Caucasian T1D patients carry a genetic predisposition (human leukocyte antigen (HLA) alleles) which, combined with environmental triggers, results in manifestation of the disease. Gliadin exposure has been linked to the expression of T1D in human and animal studies. Recent studies indicate that gastrointestinal symptoms in T1D patients are associated with increased intestinal permeability and zonulin levels which occur prior to the onset of GI complications. Human studies indicate that nondiabetic family members (with similar inheritance) commonly have increased zonulin and intestinal permeability.

Liver disease—Obese adolescents and juveniles with nonalcoholic fatty liver disease had higher zonulin levels than age, gender, and BMI-matched controls.

Multiple sclerosis (MS)—It has been demonstrated that disruption of intestinal homeostasis is an early and immune-mediated event in an animal model of MS. Transfer of autoreactive T-cells from mice with experimental autoimmune encephalomyelitis (EAE) increased the infiltration of proinflammatory Th1/Th17 cells and a reduced regulatory T-cell number in the gut lamina propria, Peyer’s patches, and mesenteric lymph nodes. Altered T-cell signaling increased expression of zonulin and intestinal permeability, which altered intestinal morphology. The intestinal changes were seen at 7 days (preceding the onset of neurological symptoms) and at 14 days (at the stage of paralysis) after T-cell immunization. 

In many disorders associated with elevated zonulin and increased intestinal permeability, such as Crohn’s disease, studies indicate that asymptomatic close relatives may often have increased zonulin and intestinal permeability, and that most develop symptomatic disease within a few years.

Normalization of zonulin levels: 

Probiotic use has been shown to reduce serum and fecal zonulin levels. Restoration of the gastrointestinal mucosal barrier may include dietary changes, treatment of dysbiosis, digestive supports, and anti-inflammatory supplements which may include quercetin, vitamin C, curcumin, gamma-linoleic acid, omega-3 fatty acids (EPA, DHA), and aloe vera. Other nutrients such as zinc, beta-carotene, pantothenic acid, and L-glutamine provide support for regeneration of the GI mucosa. Glutamine has specifically been shown to improve intestinal barrier function in high-stress patients. The amino acid taurine has been shown to have anti-inflammatory actions both in vivo and in vitro. Increased fiber consumption may improve mucus production in the large and small intestine, as fiber consumption increases bacterial synthesis of short-chain fatty acids which improve intestinal barrier integrity. 

The dysregulation of the zonulin signaling pathway disrupts normal gut barrier function and alters immune responses. High levels of serum zonulin may alert clinicians to the presence of increased intestinal permeability in their patients. As zonulin is the only known regulator of reversible intestinal permeability, the biomarker may be used to monitor therapeutic interventions designed to restore gut barrier function.

What does it mean if your Zonulin Family Peptide result is too high?

The clinical significance of an elevated zonulin family peptide is unknown. It may relate to increased intestinal permeability and results should be confirmed with a follow up lactulose/mannitol Intestinal Permeability Assessment.

Elevated fecal levels of a zonulin family protein (ZFP) have been associated with metabolic syndrome and obesity; conditions that have been linked to increased intestinal permeability ("leaky gut"). [L]

In this study, serum and fecal zonulin were significantly higher in patients with Crohn’s disease compared to ulcerative colitis. No association of serum or fecal zonulin was found with respect to IBD localization and behavior. The only difference was found with respect to smoking. Both the IBD cohort and healthy smokers showed significantly higher fecal zonulin levels (median 203 ng/mL) compared to non-smokers (median 35.8 ng/mL). Fecal and serum zonulin levels are elevated in patients with active Crohn’s disease but not with ulcerative colitis. High fecal zonulin levels in smokers irrespective of IBD point to the significant and undesirable up-regulation of gut permeability in cigarette smokers.

Studies on athletes show a reduction in stool zonulin family peptide levels with colostrum and probiotics.

What does it mean if your Zonulin Family Peptide result is too low?

A normal or low zonulin family peptide finding does not necessarily rule out intestinal permeability. A follow up lactulose/mannitol Intestinal Permeability. Assessment should be considered if intestinal permeability is suspected. 

Frequently asked questions

Unlock Your Health Journey with Healthmatters.io! Ever wished for a one-stop digital health haven for all your lab tests? Look no further! Healthmatters.io is your personalized health dashboard, bringing together test reports from any lab. Say goodbye to scattered results—organize and centralize your lab data effortlessly. Dive into the details of each biomarker and gain insights into the meaning behind your medical test data.

Join the community of thousands who've transformed the way they understand their lab results. Experience the joy of having all your lab data neatly organized, regardless of where or when the tests were done.

For our professional users, Healthmatters.io is a game-changer. Revel in the intuitive tools that not only streamline analysis but also save valuable time when delving into your client's lab report history. It's not just a dashboard; it's your gateway to a smarter, more informed health journey!

Healthmatters.io personal account provides in-depth research on 4000+ biomarkers, including information and suggestions for test panels such as, but not limited to:

  • The GI Effects® Comprehensive Stool Profile,
  • GI-MAP,
  • The NutrEval FMV®,
  • The ION Profile,
  • Amino Acids Profile,
  • Dried Urine Test for Comprehensive Hormones (DUTCH),
  • Organic Acids Test,
  • Organix Comprehensive Profile,
  • Toxic Metals,
  • Complete Blood Count (CBC),
  • Metabolic panel,
  • Thyroid panel,
  • Lipid Panel,
  • Urinalysis,
  • And many, many more.

You can combine all test reports inside your Healthmatters account and keep them in one place. It gives you an excellent overview of all your health data. Once you retest, you can add new results and compare them.

If you are still determining whether Healthmatters support your lab results, the rule is that if you can test it, you can upload it to Healthmatters.

While we do talk about popular labs, we welcome reports from lots of other places too. It's as simple as this: if you can get a test done, you can upload it to Healthmatters. We can interpret results from any lab out there. If laboratories can analyze it, we can interpret it.

Still on the hunt for a specific biomarker? Just tell us, and we'll add it to our database. Anything from blood, urine, saliva, or stool can be uploaded, understood, and tracked with your Healthmatters account!

There are two ways to add your test reports to your healthmatters.io account. One option is to input the data using the data entry forms. The other method is to utilize our "Data entry service."

Our data entry forms offer an easy, fast, and free way for you to input the reports yourself. Self-entry allows you to add an unlimited number of reports at no cost. We make the self-entry process user-friendly, providing dozens of templates that pre-populate the most popular laboratory panels and offering instant feedback on entered values.

For those who prefer assistance, we offer a "Data entry service" to help you input your data. Simply attach an image or file of your lab test results, and a qualified team member from our data entry team will add the results for you. We support various file types, including PDFs, JPGs, or Excel. This service is particularly useful if you have many reports to upload or if you're too busy to handle the data entry yourself.

Our special data entry service makes it easy to add your results to your private dashboard. Just attach an image or a file of your lab test results, and our skilled data entry team will do the work for you. It's all done by humans, ensuring that your data is entered accurately and with personal care for each client.

Depending on your account, the data entry service can be included for free or come at an additional cost of $15 per report.

For users on the Complete monthly plan, the first report is entered free of charge, and each additional report incurs a fee of $15.

Unlimited account holders enjoy the entry of ten reports without charge. Subsequent reports are subject to a $15 fee per report.

Additionally, users on the Complete plan can upgrade to a yearly subscription from the account settings. The annual subscription includes a data entry service for five reports.

The Unlimited plan is a one-time purchase for $250, and it covers your account for a lifetime with no additional payments.

For the Complete plan, the cost is $15 per month. You have the flexibility to cancel it anytime through your account settings, ensuring no further payments. To avoid charges, remember to cancel at least a day before the renewal date. Once canceled, the subscription remains active until the end of the current billing cycle.

Additionally, you can upgrade to the yearly Advanced plan from within your account. The annual cost is $79, and it comes with a data entry service for five reports.

You can always upgrade to a lifetime version with a prorated price from a monthly or yearly subscription.

Simply log in and navigate to your account settings to cancel your subscription. Scroll down to locate the 'Cancel' button at the bottom of the page. Ensure you cancel at least one day before the renewal date to prevent any charges. Once cancellation is requested, the subscription remains active until the conclusion of the current billing cycle.

Unlocking the insights from your lab tests has never been this intuitive! We've crafted multiple ways for you to navigate your data, whether you're glancing at a single report or delving into a treasure trove of testing data.

1. Graph View:

Dive into a visual journey with our biomarker graphs, showcasing over 40 data points. Combining years of results unveils trends, empowering you to make informed decisions. Our visualization tools make it a breeze to compare and understand changes over time, even if your results are from different labs. A search function and filters simplify the exploration of extensive data, allowing you to focus on what needs attention.

2. All Tests View

Get a quick grasp of your test reports in minutes! Explore neatly organized reports on a timeline, highlighting crucial details like dates, critical results, and lab/panel names. Each report opens up to reveal in-depth descriptions and additional recommendations for each biomarker. The history of previous results is just a click away, and you can download a comprehensive report for deeper insights. Color-coded and user-friendly, it's designed for easy reading, understanding, and navigation.

3. Table View:

For a holistic view of all biomarkers side by side, our table view is your go-to. Results are neatly displayed in a categorized and dated table, ideal for those with an extensive test history. Utilize sorting, filters, and color-coding to enhance your analysis and gain extra insights.

Experience the power of clear, organized data visualization with Healthmatters.io — your key to understanding and taking charge of your health journey!

Yes, you can download information from your account. We can compile your labs into a CSV file. To download all your labs, you can go to Account Settings, and at the bottom of the page, you will find a link to download your information.

Yes, you can print your report. To do so, navigate to "All tests" and open the report you wish to print. You'll find a print button in the right corner of the report. Click on it, and your browser's print window will open. If you prefer to print in a bigger typeface, adjust the scale using the print window settings.

A personal account is all about keeping your own lab test results in check. It's just for you and your personal use.

The professional or business account is designed for health professionals who wish to track and organize their clients' laboratory results.

Use promo code to save 10% off any plan.

We implement proven measures to keep your data safe.

At HealthMatters, we're committed to maintaining the security and confidentiality of your personal information. We've put industry-leading security standards in place to help protect against the loss, misuse, or alteration of the information under our control. We use procedural, physical, and electronic security methods designed to prevent unauthorized people from getting access to this information. Our internal code of conduct adds additional privacy protection. All data is backed up multiple times a day and encrypted using SSL certificates. See our Privacy Policy for more details.