Dr. Michael Ruscio, DC is a clinician, Naturopathic Practitioner, clinical researcher, author, and adjunct professor at the University of Bridgeport. His work has been published in peer-reviewed medical journals and he speaks at conferences around the globe.
Pros and Cons of Zonulin and Other Leaky Gut Tests
Leaky gut syndrome occurs when the lining of the small intestine becomes disrupted, allowing potentially harmful substances to enter the bloodstream and causing a variety of negative symptoms.
Several leaky gut tests exist, but none is clinically validated.
Of the existing tests, zonulin testing is popular in functional medicine.
Increased zonulin levels correlate with health and disease and are the only recognized biomarker that contributes to intestinal permeability (leaky gut).
However, zonulin testing may not be as useful in practice as we would hope.
The lactulose-mannitol test is another widely used leaky gut syndrome test, but at this stage, it’s not very helpful for clinical decision making.
Leaky gut syndrome can be treated naturally with nutrition and lifestyle-related interventions and probiotics, with or without testing.
Leaky gut syndrome (also known as increased intestinal permeability) occurs when the tight junctions between the cells of your small intestine lining become too loose, allowing large, undigested food particles and other potentially harmful substances to enter your bloodstream. The end result can be systemic (body-wide) inflammation.
Leaky gut is associated with many digestive symptoms (bloating, gas, diarrhea, and constipation), but can also lead to brain fog, joint pain, skin issues (eczema, psoriasis, and acne), fatigue, and depression, just to name a few.
So, how do you know if you have a leaky gut? Well, you can consider getting a zonulin test, an increasingly popular option . Zonulin is a family of proteins that regulate the tight junctions of the small intestine. Zonulin levels can be measured in the blood or stool but zonulin antibodies can also be measured. However, zonulin levels don’t always seem to correlate with improvements in symptoms following leaky gut treatments, and these tests are not clinically validated.
The lactulose-mannitol (L:M) test is another widely used test to assess gut barrier function. It measures the levels of the sugar molecules lactulose and mannitol in the urine. Lactulose isn’t normally absorbed in the small intestine, but mannitol is, so a higher L:M ratio may indicate a leaky gut. At this time, though, L:M testing lacks standardization and is more useful in research than in clinical practice.
In addition to zonulin and L:M testing, there are a variety of other gut barrier function biomarkers. At this time, tests for these biomarkers are only useful for research purposes and haven’t yet been validated for use in clinical practice.
If you have symptoms of poor gut health or any of the symptoms listed above, and haven’t identified another cause, some degree of leaky gut is likely, and you may not need a test to confirm this in order to start healing your gut lining [2, 3].
In this article, we’ll discuss the available leaky gut syndrome tests, how they work, and how to know if you need one.
What Is Leaky Gut Syndrome?
Before we dive into leaky gut syndrome testing, let’s review leaky gut. Your small intestine is arguably the most important section of your gastrointestinal tract because it houses the majority of your immune system and is responsible for much of your nutrient absorption. Unfortunately, it’s also the most prone to damage.
The small intestine lining (barrier) is made up of a single layer of epithelial cells that separate the contents of your gut from the rest of your body . These small intestine cells are connected by proteins that make up tight junctions, adherens junctions, and desmosomes (structures for cell-to-cell connection) .
The permeability of this epithelial barrier is regulated in two main ways:
The transcellular pathway regulates the movement of large molecules like antigens (foreign proteins) through cells.
The paracellular pathway regulates the movement of small molecules, ions, and solutes between intestinal epithelial cells and also prevents the passage of large molecules like undigested food particles and foreign proteins.
The paracellular pathway is regulated by tight junctions, which are disrupted in leaky gut. An increase in paracellular permeability and epithelial damage can allow for the excessive entry of dietary and microbial antigens (any substance that triggers an immune response) into the bloodstream, causing widespread inflammation .
The longer the leaky gut continues, the more likely it is to contribute to an inflammatory cycle that can then affect the rest of the body, further increasing inflammation and worsening intestinal permeability .
Leaky gut isn’t yet accepted by the medical community as a diagnosis, but is recognized widely in scientific research and is associated with a number of health problems [5, 6, 7]. Let’s review what can cause a leaky gut.
What Causes Leaky Gut?
Leaky gut can be caused by many different factors:
Use of NSAIDs (non-steroidal anti-inflammatory drugs), aspirin, and some prescription medications [14, 15, 16]
Intestinal dysbiosis (imbalanced gut bacteria) [17, 18, 19, 20]
While each of these alone can lead to leaky gut, in the clinic at the Ruscio Institute for Functional Medicine we find most people have multiple contributing factors and experience a wide variety of negative symptoms.
What Are the Symptoms of Leaky Gut?
When you think of a leaky gut, digestive symptoms may immediately come to mind. Common digestive symptoms include [21, 22, 23, 24]:
Some people with leaky gut may not have any digestive complaints at all but rather struggle with other symptoms like:
Having one of these symptoms doesn’t necessarily equate to having a leaky gut, but if you experience several of these, a leaky gut may indeed be an issue. If you’re considering leaky gut syndrome testing, read on to learn about the available tests and understand why this type of testing may not be needed.
What’s the Best Leaky Gut Syndrome Test?
There are several types of leaky gut syndrome tests. Let’s take a look at the specifics of each:
Zonulin is usually referred to in the singular, but it’s actually a family of proteins created in the cells of the small intestine and liver that has been shown in multiple studies to regulate the tight junctions of the small intestine and to increase intestinal permeability [6, 18, 53].
Zonulin is a gatekeeper so to speak, so when the gut is leaky, the body tries to compensate by further increasing zonulin levels to protect the small intestine [5, 54]. This increase in zonulin may further increase intestinal permeability, which can ramp up inflammation leading to the above-mentioned inflammation-leaky gut cycle. Currently, increases in zonulin are the only recognized biomarker that contributes to intestinal permeability [5, 54].
It may seem desirable to test zonulin levels, and research does suggest zonulin correlates with health and disease , but zonulin may also be one of the ways the body maintains gut barrier homeostasis (stability), so high levels may not always mean a pathological condition (such as leaky gut) is present .
Zonulin levels can be tested in the serum (blood) and in the stool via the enzyme-linked immunosorbent assay (ELISA) method, however the validity of these tests is questionable:
Two observational studies and one literature review found the ELISA test detected a variety of proteins structurally similar to zonulin, casting doubt on whether only zonulin levels are being measured [56, 57, 58].
Serum zonulin levels are known to fluctuate widely throughout the day, so a single measurement may not be a great reflection of what’s going on in the gut .
Other observational research has found the following with regard to serum zonulin levels:
No significant difference between healthy people and those with IBS (irritable bowel syndrome) and functional dyspepsia .
Higher levels correlate with poor metabolic health and being overweight, but do not correlate with gastrointestinal symptoms or diseases .
Higher levels are found in those with IBS and celiac disease, and correlate with stool frequency and dissatisfaction, but don’t correlate with IBS severity .
There may be more research in support of blood zonulin than stool zonulin testing, but that’s partly just due to the fact that more studies have been done on blood zonulin testing . It appears that neither blood nor stool zonulin are very reliable though when it comes to assessing leaky gut:
One study found stool zonulin correlated with the L:M test, while blood zonulin didn’t , but another study found no such correlation .
Blood zonulin has been found to correlate more with disease activity when compared to stool zonulin , but another study found stool zonulin correlated somewhat with disease activity .
Overall, the research indicates that zonulin testing, whether blood or stool, isn’t the most accurate indicator of leaky gut. In fact, several studies have found various nutrition-related strategies and weight loss to significantly improve symptoms despite no change in zonulin levels [66, 67, 68, 69].
The lactulose-mannitol test (L:M), also called the dual sugar test, involves the oral ingestion of lactulose and mannitol and then measurement of their levels in the urine. This helps to test barrier function.
Mannitol is a small sugar molecule that’s routinely absorbed in the small intestine, so it’s used as a reference molecule. Lactulose, on the other hand, is a larger molecule that’s not normally absorbed in the small intestine, so high amounts of lactulose in the urine are thought to be indicative of leaky gut [4, 7, 70].
A higher ratio of L:M may indicate worse leaky gut, and one systematic review and meta-analysis found the L:M ratio to be significantly higher in unhealthy patients when compared to healthy controls . In addition, patients with untreated and active disease had a higher L:M ratio, indicating that this test may also correlate with disease severity .
While early research is promising, the L:M test is not yet ready for use in clinical practice for several reasons:
The permeability pathways of lactulose and mannitol in the gut are unclear .
Small intestinal bacterial overgrowth (SIBO) may influence the test results (colonic bacteria that have moved into the small intestine may ferment lactulose and mannitol, possibly altering results) .
Another type of leaky gut syndrome test measures the antibodies against proteins and other molecules involved in gut barrier integrity, such as zonulin and other tight junction proteins, and lipopolysaccharide (LPS). LPS is a bacterial toxin that can leak into the blood when increased intestinal permeability is present .
This type of test is based on the idea that the immune system creates antibodies that can attack various gut barrier proteins to promote leaky gut, so the detection of these antibodies could be a sign of leaky gut.
One observational study found loose correlations between inflammatory bowel disease (IBD) and gut barrier antibodies that could contribute to leaky gut , and another found zonulin antibody testing to be more stable than blood zonulin testing . However, leaky gut antibody tests may lack validation, so more research is needed before using these types of tests in clinical practice [59, 75].
It’s also important to note that there are some substantial conflicts of interest regarding lab companies and leaky gut antibody research. For example, one of the researchers involved in a number of the published studies on antibody testing for leaky gut is an advisor for a prominent lab company that sells these same tests.
In addition, another lab company that sells this type of antibody testing states on their website that the clinical utility of their testing hasn’t been well-established and should only be used for informational purposes.
Other Leaky Gut Syndrome Tests
There are a variety of other biomarkers that may theoretically be helpful for detecting leaky gut:
Lipopolysaccharide (LPS, bacterial byproducts) has been associated with high zonulin levels 
Lipopolysaccharide binding protein (LBP) has been found to correlate with the L:M test 
Intestinal fatty acid binding protein (I-FABP) measures the turnover of intestinal cells, with high levels possibly indicating intestinal cell damage [4, 76]
Citrulline levels may decrease when intestinal permeability is present 
It should be noted that none of these biomarker tests have been validated for use in clinical practice .
Healing Your Symptoms Without Testing
Adrian had chronic and constant brain fog, joint pain, and fatigue for several years. He had seen a variety of healthcare providers, both conventional and naturopathic, and experienced some improvement but never really felt well until he implemented the Great-In-8 step-by-step gut-healing plan in Healthy Gut, Healthy You. Adrian didn’t report a formal diagnosis of leaky gut, but his symptoms were indicative of it.
The great news here is he didn’t need a test to heal his body. Research has shown that an elimination diet and the addition of probiotics can significantly improve leaky gut symptoms . Other studies have shown prebiotics , a low FODMAP diet , and other diets [66, 67] can improve leaky gut symptoms as well.
I recommend starting with the Paleo diet and focusing on important lifestyle factors like exercise, sleep, and stress. If you don’t experience complete healing of your symptoms after several weeks from these interventions, then add in probiotic supplements and see how you feel.
Leaky Gut Syndrome Tests May Not Be Necessary
Leaky gut can lead to a variety of troublesome symptoms like digestive distress, brain fog, joint pain, and skin issues. If you’re experiencing these symptoms, you may be considering testing to confirm a leaky gut.
But while leaky gut syndrome testing is available, it isn’t necessarily helpful. It’s important to remember that the results of a leaky gut syndrome test won’t change the way the condition is treated and you can begin to improve your health with simple, cost-effective strategies.
If you think you’ve got a leaky gut, consider forgoing the testing; instead, try implementing diet and lifestyle-related strategies and add probiotics. If you still have symptoms, consider following the step-by-step plan outlined in Healthy Gut, Healthy You or visit us at the Ruscio Institute for Functional Healthcare.
The Ruscio Institute has developed a range of high-quality formulations to help our patients and audience. If you’re interested in learning more about these products, please click here. Note that there are many other options available, and we encourage you to research which products may be right for you.
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