Intestinal Permeability Tests to Assess Gut Health

What is Intestinal Permeability?

Intestinal permeability (or intestinal barrier penetration) is most commonly known as leaky gut.

It is a digestive condition in which potentially harmful substances — such as bacteria, undigested proteins, infectious organisms and bacterial fragments — inappropriately leak through the wall of the small intestine.

When this gut barrier function is compromised, these substances can get into the bloodstream or lymphatic system where they do not belong.

This sets off an immune response and can aggravate and contribute to a number of gastrointestinal conditions such as celiac disease, Crohn’s disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and ulcerative colitis. (Bischoff et al., 2014)

Having a leaky gut can potentially set off a chain reaction that might impact the body in a number of ways, including triggering or worsening conditions ranging from asthma, eczema, psoriasis, rheumatoid arthritis, and food allergies to autoimmune disease, chronic fatigue syndrome, obesity, and both type 1 diabetes and type 2 diabetes. (König et al., 2016)

While there is no universal cause for a leaky gut, some proposed factors are the above-mentioned gastrointestinal conditions, intestinal infection, ingestion of allergenic foods such as gluten, and certain drugs or radiation therapy. Because gut health is tied to overall health, maintenance of the intestinal barrier function is crucial for a strong immune system — dysfunction is a risk factor for a variety of disorders and diseases. (König et al., 2016)

However, the link between leaky gut and issues outside of the digestive system is hotly debated.

Many health practitioners cite evidence that "increased intestinal-barrier permeability to large molecules plays a key role in the development of various inflammatory and autoimmune disorders, including Parkinson’s disease." (Vojdani, 2013)

Others in the medical community, such as the Canadian Society of Intestinal Research, argue that leaky gut syndrome is a condition for which there is no medical evidence.

Differences aside, both camps agree that more scientific studies are needed to better understand the causes and effects of increased intestinal permeability and how to treat any dysfunctions associated with it.

How to Assess Leaky Gut

There are a growing number of tests that claim to assess intestinal permeability successfully, but many have been debunked.

Outlined here are the more reliable methods with scientifically based support. While these tests can often be ordered online and administered at home, it's advised to seek the supervision of a qualified healthcare practitioner to ensure appropriate interpretation and treatment.

Lactulose/Mannitol Test

Type of Test: Urine

The lactulose/mannitol test is a non-invasive way to assess gut permeability and is also used as an index of recovery from inflammatory bowel disease (IBD) and autoimmune diseases such as celiac disease. (Sequeira et al., 2014)

This method measures the ability of two sugar molecules  — mannitol, which is a small, easily digested molecule, and lactulose, a somewhat larger molecule that is not easily absorbed — to penetrate the intestinal mucosa, also known as the intestinal epithelial barrier.

The first step is to provide a urine sample. Next, you drink a mixture with a pre-measured amount of lactulose and mannitol to introduce these sugar molecules to your system. After around six hours, you provide another urine sample. Once these specimens are collected, the lactulose-mannitol ratio is determined to help identify the level of intestinal permeability.

Pros & Cons

Lactulose/mannitol testing is simple, cost-effective, and offers a fast turnaround time of about one week. It has long been a go-to standard for gauging small intestinal permeability, but it should be noted that there are some drawbacks.

• It does not analyze the passage of antigenic molecules that can specifically trigger the immune system. This information could help to understand associated conditions better.
• It also doesn't provide data on the gut barrier's permeability to larger molecules, which would shed light on whether food and other larger substances could get through the gut wall. (Vojdani, 2013)
  

Research also suggests that comparison of the two sugars should include consideration of the absolute amounts of each sugar that are absorbed rather than just the ratio of the two —  the amounts of each may be influenced differently by disease. (Sequeira et al., 2014)

Also, while most lactulose/mannitol tests follow a six-hour waiting period between urine collections, more recent clinical studies indicate that the optimal period for urine collection is between 2½ to 4 hours post-dosage to minimize the risk of error. (Sequeira et al., 2014)

Antigenic Permeability Test

Type of Test: Blood

An antigen is a toxin, bacteria, virus, or other substance that stimulates the production of an antibody (i.e., an immune response) in the body. This blood test analyzes antibodies against several molecules including lipopolysaccharides (LPS), the actomyosin network (a protein complex that maintains the resilience of tight junctions), and tight junction proteins occludin and zonulin, which regulate the permeability between cells in the gut wall. (Thomas et al., 2006)

Unlike lactulose/mannitol tests, this screening isn't limited to small sugar molecules. It identifies large antigenic molecules that are similar in size to food proteins and challenge the immune system. Furthermore, an antigenic permeability test identifies the route of molecules passing through the paracellular pathway between cells as well as the transcellular pathway through the cells.

When antibodies against LPS are detected on the test, it indicates that a larger molecule has gotten past the intestinal barrier, demonstrating a potential lapse in barrier function given that LPS are linked to increased gut permeability. (Maes et al., 2007)

Antibodies to the actomyosin network also illustrate potentially abnormal intestinal permeability through the cells (transcellular pathway) while antibodies against occludin and zonulin show that tight junctions may not be working at peak function (paracellular pathway).

Pros & Cons

An antigenic permeability test offers a deeper dive into identifying the areas where the gut might be "leaking" both between cells and through cells. Measuring this data can be highly useful since increased paracellular and (possibly) transcellular permeability often results in gut barrier dysfunction. (Wang, Llorente, Hartmann, Yang, Chen & Schnabl, 2015)

While this test measures zonulin levels, it's important not to confuse it with zonulin tests. Although ubiquitous, these tests are not reliable when attempting to determine the permeability of the intestinal barrier due to the fluctuations in zonulin. (Vojdani, Vojdani & Kharrazian, 2017)

Indeed, an antigenic test offers a more robust intestinal permeability assessment, but if you do not like needles, having blood drawn is an obstacle to overcome.

Zonulin Test

Excessive production of zonulin causes the intestine’s tight junctions to stretch inappropriately, causing toxins and bacteria to leak into the bloodstream. A zonulin test can show if your zonulin levels are higher than normal.  

Pros & Cons

Zonulin levels are often found to not correlate with the more valid Lactulose-Mannitol test, so its clinical validity has been called in to question.

Zonulin levels may also fluctuate dramatically in an individual, such that the result of a test may not be an accurate representation of intestinal permeability

Breath Test for SIBO

A breath test can diagnose SIBO which is often associated with leaky gut. This is certainly not a direct measure of leaky gut and results should always be considered as part of a large context of your health.

Pros & Cons

Breath tests themselves may also produce false negatives so this must also be considered.

Interpretation of results often depends on the skill of the practitioner.

The cost of testing, the preparation diet and the testing process may be barriers.

Comprehensive Stool Analysis

Type of Test: Stool

A comprehensive stool analysis detects the levels of beneficial bacteria and pathogenic bacteria and yeast (such as candida) in the gut, assesses intestinal immune system function, and ascertains whether or not there's inflammation.

In other words, a stool sample can offer a snapshot of your microbiome and whether or not your body produces enough enzymes to break down food properly. It also may show whether you have dysbiosis that might contribute to digestive issues or systemic health issues.

It is not a direct measure of leaky gut, but may indicate an issue if there is significant dysbiosis. As with the SIBO breath tests, the results should always be interpreted as part of a larger context of your health.

Pros & Cons

Given that many ailments stem from digestive issues and poor nutrient absorption, balanced gut function is imperative. (Wu & Wu, 2012)

This test not only pinpoints the amount of beneficial bacteria in the GI tract necessary for proper digestion, but it also identifies pathogens and various inflammation and immune markers needed to determine treatment.

However, depending on the lab and the methods used, some species of bacteria are not reported on or may not be detected if culture-based methods are used for quantification.

It also might not be the most convenient or comfortable test — some tests require multiple samples. Conditions like chronic constipation may make it difficult for an individual to provide a sample.

There are also a number of other challenging requirements such as discontinuing use of certain medications and supplements. Cost is also prohibitive for some people, depending on insurance coverage.

Treating Leaky Gut

Although it's not officially recognized as a medical term, leaky gut is a real problem that can reveal itself in painful gastrointestinal issues, food sensitivities, and a host of other conditions. The good news is that scientific research continues to flourish in this field and there are ways to treat some of the underlying issues.

For example, clinical studies show that probiotics not only help maintain normal function of the intestinal barrier, but they also protect tight junctions and intestinal mucosa from toxins, allergens, and pathogens. (Rao & Samak, 2013)

In addition, taking a diverse-yet-specific combination of probiotics and prebiotics (known as synbiotics) can promote gut health. (Vyas & Ranganathan, 2012)

What's more, the scientific community understands that "it is now evident that the gut microbiota has a profound effect on the host immune system and can affect autoimmune-related diseases both within and outside the gut." (Wu & Wu, 2012)

No universal marker gives a definitive answer on the leakiness of the small intestine, but getting informed and taking action is an essential step toward a solution.

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