‘Leaky gut’ is gaining more attention by the day, although it is not a recognized medical condition. This is because studies are increasingly associating various diseases with the state of our gut. Increased intestinal permeability, also known as ‘leaky gut,’ has been linked to autoimmune diseases, chronic fatigue syndrome, allergies, and even depression. In this post, you will learn more about the intestinal barrier, factors that may disrupt it, and ways in which you can improve your gut health.
The main function of the gut is to absorb nutrients from food. However, the gut also has another important function – to keep harmful things such as bacteria (good as well as bad), toxins, and food antigens (inflammatory agents) out and away from the rest of the body .
The intestinal barrier basically separates the gut content from the body. It is made of a single layer of cells (epithelial cells, sensing cells, and cells that produce enzymes and neurotransmitters).
These cells are linked by tight junction (TJ) proteins .
The intestinal/gut barrier is amazing! It :
- covers a surface of about 400 m2
- uses approximately 40% of the body’s energy expenditure
- is renewed approximately every 5 days
Research suggests that many other factors help support this barrier :
- Beneficial gut bacteria
- Antimicrobial molecules
- Immunoglobulins (especially IgA)
Studies have found that gut bacteria, in particular, have many beneficial roles in maintaining the intestinal barrier. They :
- Help with the digestion and absorption of nutrients
- Prevent colonization by harmful bacteria
- Stimulate immunity
Is leaky gut a real issue? Research that’s increasingly accumulating on the subject suggests that it may be. However, leaky gut is not recognized as a legitimate medical issue because, at this point, there is simply not enough evidence to support it.
On one hand, there is a lot that scientists still don’t know or understand about the gut and the microbiome within it. On the other hand, there is a lot of speculation that has been derived from small-scale human or animal studies. In this article, we will try to objectively review the research on this subject.
The theory is fairly simple. When there are abnormalities in the intestinal barrier, the intestinal permeability increases. This potentially means that more of the gut content can pass/leak through, which is referred to as “leaky gut” .
Some scientists think that when the gut is leaky, gut bacteria and their products may escape the gut, which could potentially produce inflammation and cause tissue damage. Similarly, food-derived antigens (proteins or partially digested proteins) could pass through the gut and promote both local or whole-body immune responses .
On the molecular level, researchers have found zonulin, a protein that causes tight junctions to open. When tight junctions open, intestinal permeability increases. Studies suggest that some agents, such as bacteria and gluten, may be able to cause ‘leaky gut’ by increasing zonulin [3, 4].
Proponents of Leaky Gut Syndrome state that if you suffer from leaky gut, you may experience one or more of the signs and symptoms listed below:
- Food sensitivity
- Autoimmune disease
- Thyroid problems
- Skin conditions (inflammatory, acne)
However, none of these symptoms is specific, and they can all have alternative causes. In addition, skeptics stress that leaky gut is likely to be only a symptom of some of the conditions listed above (e.g. IBD) and not a valid medical condition in its own right.
There are a couple of tests available that test for intestinal permeability. However, these tests are not recognized by mainstream medicine because there is not enough research to back them up.
This test has been used the longest in both human and animal studies .
Lactulose and mannitol are sugars that aren’t broken down in the digestive tract. Mannitol is smaller and gets absorbed through the gut. Lactulose is larger and is only absorbed if there is increased intestinal permeability. Levels of lactulose vs. mannitol can then be measured in the urine .
However, there is a question of how reliable this test is. In a study of people with celiac disease, a condition which in theory should go hand in hand with increased intestinal gut permeability, a lactulose-mannitol test was normal for more than half of the 29 patients .
In addition, studies suggest that decreased gut flow and impaired kidney function can affect the results. The test is also unsuitable for patients on blood transfusion since mannitol is used in the storage solution of banked blood .
If you do decide to take this test, remember to take your result with a grain of salt. A normal result on this test doesn’t mean that you don’t have a medical condition, and similarly, an abnormal result doesn’t mean that you have one.
Zonulin is a protein that causes tight junctions to open. Some scientists suggest that more zonulin may mean that there is higher intestinal permeability. They also suggest that zonulin may be a marker for leaky gut and autoimmune diseases that are caused by issues in the zonulin pathway [3, 4].
However, while blood tests for zonulin recently became available, there is not much that we actually know about how useful this test is or what the normal ranges in different populations may be. So it would be best to approach this test as highly investigational.
With an intact gut, the immune system should not be exposed to the gut content. Therefore there shouldn’t be a lot of antibodies against foods. By inference, if you have a lot of antibodies against various foods, you likely have some intestinal permeability.
While the logic here seems solid, clinical studies that would show a cause and effect relationship between leaky gut and food sensitivities are missing.
On the plus side, you will likely benefit from knowing which foods you are allergic to, if any.
The section below is based on limited evidence from small-scale human and animal studies. While many of these studies are intriguing, large-scale clinical trials are needed to corroborate their findings!
Animal studies have found that unhealthy diets can create an imbalance in the intestinal barrier. These diets include:
- Diets low in fiber 
- Diets high in saturated fats 
- Diets high in fats and sugars (a typical Western diet) 
- Diets high in processed food containing emulsifiers 
In an observational study that looked at 100 pregnant overweight women, women who ate more healthily (more omega-3 fatty acids, fiber, vitamins, and minerals) tended to have lower intestinal permeability (measured by zonulin) .
Lectins are proteins that are especially concentrated in seeds (grains, legumes, nuts) and tubers (potatoes).
Lectins can be beneficial by stimulating the immune system. However, research suggests they may also bind to the surface of gut-lining cells and disturb the gut barrier .
Furthermore, in human gut cells, some dietary sources of lectins such as wheat may directly open tight junctions by increasing zonulin. However, the degree of this created intestinal permeability is much higher in gut cells from people with celiac disease compared to gut cells obtained from healthy people .
In addition, rats who experienced maternal separation in youth are also more prone to leaky gut when they experience social stress as adults !
A human study in 29 intensive care patients showed that there is increased intestinal permeability 72 to 96 hours after trauma. The more severe the injury, the greater the increase in gut permeability .
In the same study, patients with a larger increase in intestinal permeability were at a higher risk of whole-body inflammation, multiple organ dysfunction, and infections .
Similarly, studies show that burn injuries increase intestinal permeability in both animals and humans .
Exercise may increase intestinal permeability. While we exercise, blood goes into the muscles and away from the stomach, and the supply of oxygen to the gut is reduced.
Studies suggest that when the blood supply to the gut is reduced by more than half, intestinal permeability increases. For reference, people exercising at 70% maximum capacity have a 60 to 70% reduced blood flow to the gut. At 100% of maximum capacity, the blood flow is reduced by 80% .
Some scientists think that people who exercise at high intensities for longer periods may have compromised gut barrier integrity. This would put them at a greater risk of chronic inflammation and diseases .
In a study of 20 athletes, running at 70% capacity increased intestinal permeability, which is more pronounced in those who already suffered from gut-related symptoms .
Cycling at 70% capacity increased gut leakiness and the number of allergens reaching the bloodstream in another study with 10 people .
However, a study in 11 well-trained athletes showed that the gut adapted to exercise. As a result, the intestinal permeability was not affected .
This suggests the gut barrier may be ‘trained’ akin to training your muscles.
Alcohol may disrupt intestinal barrier function and increase gut permeability .
A study in 36 alcoholics suggests that alcoholics have higher gut permeability, which can persist for up to 2 weeks after drinking .
Another study showed that one week of moderate consumption of red wine was safe in healthy people. However, it increased intestinal permeability in 14 patients with inactive inflammatory bowel disease (IBD) .
Some harmful bacteria, including E. coli, produce alcohol. Certain scientists propose that alcohol may be how these bacteria compromise the gut barrier function .
The intestinal barrier acts as a shield that may be modified by gut bacteria .
In a study of 100 overweight pregnant women, those with leaky gut (higher zonulin) had a lower diversity of gut bacteria .
At this point, however, this is all based on association and speculations.
Some harmful bacteria may gain access to the body by altering tight junctions to increase gut permeability .
Research suggests that other types of infections may also increase intestinal permeability. For example:
- Patients with malaria may have increased intestinal permeability (measured by a lactulose-mannitol test) .
- Tapeworm parasites can caused leaky gut in rats .
- Candida increased gut permeability in a cell-based study .
Stomach acid-suppressing drugs (PPI) may also increase gut permeability based on studies in people with liver cirrhosis . However, there are also studies that show the exact opposite. In 14 patients with cystic fibrosis, PPIs seemed to reduce gut permeability .
A study of 28 healthy female volunteers showed that vitamin C may increase intestinal permeability (lactulose-mannitol test) and that this effect may be additive when vitamin C is added to aspirin .
However, we don’t know how long-lasting or meaningful this effect is.
A study in 25 children has found that perturbed zinc balance may be associated with abnormal gut permeability (measured by a lactulose-mannitol test) .
Animal studies further suggest that vitamins (especially A and D) are necessary for the proper function of the intestinal barrier:
- A vitamin A-deficient diet impaired the intestinal barrier in rats .
- Vitamin D-deficient mice were more sensitive to gut barrier disruption [62, 63, 64].
However, additional studies are needed to check if this also applies in humans.
An observational study of 22 workers showed that night-shift workers were more prone to alcohol-induced leaky gut compared to day-shift workers .
Studies suggest that babies may naturally have a more leaky gut, which allows them to absorb immune substances from their mother’s milk .
A study with 62 preterm infants showed that those fed mostly human milk (>75%) had lower gut permeability than those receiving either low amounts or no human milk (<25%) (lactulose-mannitol test) .
The intestinal barrier may weaken as we age. Research suggests that gut permeability (measured by zonulin) is higher in older people .
However, a study with 215 adults suggested that the gut barrier does not deteriorate with age per se. Instead, in that study, it deteriorated due to chronic inflammation and minor diseases that get more common as we age .
In 18 elderly people, high gut permeability was associated with higher markers of inflammation: TNF-alpha and IL-6. It was also associated with lower muscle strength and less habitual physical activity .
Many different factors have been associated with increased gut permeability, including poor diet, stress, injury, alcohol, infections, some drugs and supplements, and inflammation. However, there is usually only a single or a couple of small-scale low-quality human studies addressing each of these factors. While the prospects are certainly intriguing and promising, large-scale human trials are needed to confirm all of these associations and any potential causal relationships.
There are scientists who suggest that a dysfunctional intestinal barrier may be an important cause of autoimmune disorders .
Human and animal studies have found an association between Increased gut permeability and:
- Type 1 diabetes [82, 83, 84]
- Autoimmune hepatitis [85, 86]
- Ankylosing spondylitis [87, 88]
- Celiac disease [89, 90]
- Rheumatoid arthritis 
- Lupus 
Proponents of this hypothesis point out that less than 10% of the people who are genetically susceptible to autoimmune disease, actually develop a disease. This means that environmental factors are important in autoimmune disease development .
In genetically predisposed people, a leaky gut may allow foreign inflammatory agents to enter the body. Then, these agents may trigger the initiation and development of the autoimmune disease .
In a clinical trial of 342 celiac disease patients on a gluten-free diet, larazotide, a drug that blocks zonulin, reduced signs and symptoms of celiac disease better than a gluten-free diet alone .
In a study with 110 patients with IBD, impaired intestinal permeability was associated with ongoing bowel symptoms. Increases in permeability correlated with more severe diarrhea .
This increase in intestinal permeability may be partially genetic. A study showed that intestinal permeability was increased in most patients with Crohn’s disease. However, it was also increased in 30% of their healthy relatives (223 healthy subjects) .
According to a similar study, the ‘gut leakiness’ in patients with Crohn’s disease and their relatives could be further exacerbated by aspirin .
A therapy that blocks TNF-alpha, an inflammation-promoting cytokine, restored intestinal permeability in a study with 23 Crohn’s disease patients .
In a small-scale study, when 36 IBS patients with a suspected food intolerance ate the offending food in question, it disrupted their intestinal barrier, as compared to controls, based on microscopic examination .
A study of 41 patients with chronic fatigue syndrome showed that more than half of the patients experienced improvement when they took supplements that purportedly help gut barrier function (such as glutamine and zinc) .
Increased gut permeability has been reported in the following diseases:
- Multiple sclerosis [106, 107, 108]
- Schizophrenia (those with a history of childhood celiac disease may have an increased risk of developing schizophrenia) [109, 110]
- Alzheimer’s disease 
- Parkinson’s disease 
At this point, it is not possible to tease apart the cause and the effect in these studies. Gastrointestinal disbalance may precede nervous system disorders and may have a role in the early development of these diseases. On the other hand, increased intestinal permeability could also be only one of the symptoms of these diseases.
Another study found that both those with autism and their first-degree relatives were more likely to have higher intestinal permeability .
A study of 41 patients with food allergies or food sensitivities showed that they had increased gut permeability. In fact, those with higher intestinal permeability had more severe allergy symptoms .
Research suggests that those with food allergies get a leaky gut after eating trigger foods. However, their gut permeability was also increased at baseline, when they were on elimination diets [122, 123, 121].
A study of 131 allergic children without symptoms on elimination diets showed that about a third had increased gut permeability .
In a small study of 15 people, those with psoriasis showed higher intestinal permeability than controls .
In another study compromised intestinal barrier was found in 18 people with eczema .
Leaky gut has been associated with type 2 diabetes in a study that compared 130 people with diabetes and 161 controls .
Similarly, another study found a link between increased gut permeability (high zonulin)and pregnancy-induced diabetes in 88 pregnant women .
In a study that included 39 children suffering from fatty liver and 21 controls, researchers found that intestinal permeability was increased in children with fatty liver. In addition, those with higher gut permeability tended to have more severe disease symptoms .
Research further suggests that patients with liver cirrhosis may also have increased intestinal permeability and intestinal barrier dysfunction .
Some scientists think that leaky gut may explain why not all heavy drinkers develop liver injury. They speculate that a leaky gut may be a necessary factor for the development of chronic liver injury among heavy drinkers .
Patients with obstructive sleep apnea (OSA) had a higher risk of having leaky gut in a small study that included 38 OSA patients and 38 controls .
In cancer-prone mice, a high-fat diet disrupted gap junction proteins, thereby increasing gut permeability. This led to increased inflammation and accelerated the development of tumors .
Small-scale human studies have found increased intestinal permeability (leaky gut) in many different medical conditions, from autoimmune and inflammatory disease to obesity and diabetes. However, larger studies are needed to confirm these findings. In addition, well-designed observational studies and clinical trials are needed to tease apart the cause and the effect for each condition. As it is now, there is not enough evidence that leaky gut may cause other non-gut related conditions. We will update the article with new information as soon as it becomes available.
As leaky gut may occur as a symptom in a number of underlying diseases, the most important thing is to work with your doctor to address any potential underlying health condition.
Some clinical studies show that addressing leaky gut may be beneficial in some gut-related conditions such as inflammatory bowel disease (IBD), diarrhea, irritable bowel syndrome (IBS), and celiac disease. However, at this point in time, there is little to no clinical evidence that addressing leaky gut could improve any particular non-gut related condition.
Much of the emerging research shows that stress may increase intestinal permeability [15, 16, 17]. Managing stress levels is one way to potentially improve the function of your intestinal barrier and your overall health.
A healthy circadian rhythm may also help keep your gut healthy .
Alcohol increases intestinal permeability and is best avoided if you have gut issues [33, 34, 35]. Even moderate consumption can increase intestinal permeability in people who have gut inflammation .
If you have certain food sensitivities (e.g. gluten), you may need to avoid offending foods. However, make sure your diet is overall healthy and well balanced, to avoid nutritional deficiencies .
In 30 people with diabetes who initially had increased intestinal permeability, 6 months of regular exercise improved leaky gut and decreased low-grade inflammation .
Swimming increased tight junction protein levels in rats .
In mice, 30 minutes of swimming per day maintained low intestinal permeability. It also prevented chronic stress-induced gut barrier dysfunction .
Make sure you are not deficient in vitamins and minerals required for proper gut barrier and immune function. These include vitamin A (retinol), vitamin D, zinc, and B vitamins.
Vitamin D helped maintain low intestinal permeability in a study with 27 Crohn’s disease patients in remission .
Vitamin D also reduced the sensitivity of the intestinal barrier to alcohol in mice .
In 12 Crohn’s disease patients in remission, those receiving zinc (10 patients) had normal gut permeability and did not relapse. Of the remaining 2 who had increased intestinal permeability, 1 relapsed .
Low levels of zinc improved intestinal permeability in a study of 58 children with diarrhea .
Probiotics may help reduce gut leakiness. Some scientists suggest they can strengthen tight junctions and restore the integrity of the intestinal barrier.
The following probiotics have helped improve ‘leaky gut’ in animal and cell studies:
- Lactobacillus rhamnosus GG [159, 160, 161, 162]
- L. acidophilus and Streptococcus thermophilus 
- L. plantarum [164, 165, 166]
- L. paracasei 
- L. gasseri 
- Bifidobacterium infantis 
- L. helveticus and B. longum 
- L. plantarum and L. reuteri 
- Bacteroides fragilis (improved autism-related symptoms in mice) 
- Escherichia coli Nissle 1917 
Prebiotics are fibers that stimulate the growth of beneficial bacteria in the gut.
In 32 people with fatty liver, a diet high in fiber reduced intestinal permeability and blood zonulin levels and improved liver function .
Prebiotic galactooligosaccharides (GOS) improved intestinal barrier function in rats with pancreatitis .
Prebiotics lowered intestinal permeability and improved tight-junction integrity in obese and diabetic mice .
A study of 51 cancer patients showed that glutamine countered the chemotherapy-induced increase in intestinal permeability .
Glutamine reduced radiation-caused gut injury and maintained lower gut permeability in rats .
No clinical evidence supports the use of any of the below-listed foods and supplements for improving gut permeability. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.
- Fermented foods (barley, soybean, kimchi) decreased gut permeability in mice and rats with IBD-like inflammation [183, 184, 185]
- Omega-3 acids helped improve gut barrier function in mice with inflammation and after chemotherapy [186, 187]
- Curcumin improved gut barrier function in rats, mice, and human cells [188, 189, 190, 191].
- Butyrate helped protect the intestinal barrier in rats with gut inflammation, and in mice fed a high-fat diet or exposed to chemotherapy [192, 193, 194].
- Melatonin improved gut barrier function in diabetic rats and rats on alcohol and in mice with IBD-like gut inflammation or mice treated with NSAIDs [195, 196, 197, 198, 199].
- Ginkgo biloba helped restore the gut barrier in rats by restoring tight junctions .
- Lipoic acid supplementation reduced intestinal permeability in post-weaning rats .
- Quercetin protected the intestinal barrier from NSAID-induced damage in rats [202, 203].
- Sulforaphane, found in high amounts in broccoli sprouts, strengthened the gut barrier in mice .
A healthy lifestyle, exercise in moderation, and a balanced diet rich in fiber may help improve gut health.
HLA-DQ is a protein found on the surface of cells that communicate with the immune system (it presents antigens to immune cells).
Studies suggest that two variants, HLA-DQ2.5 and HLA-DQ8.1 are associated with about 6-fold higher risk of developing celiac disease. About 98% of people with celiac disease have one or both of these variants [205, 206, 207].
You have HLA-DQ2.5 if you have the following variants:
You have HLA-DQ8.1 if you have the following variants:
- The HLA-DQA1*0301 variant in the HLA-DQA1 gene
- The HLA-DQB1*0302 variant in the HLA-DQB1 gene
Don’t panic if you have one of these variants. It’s important to stress that up to 40% of the general population has these variants. However, only about 1% go on to develop celiac disease. This indicates that HLA-DQ2.5 and HLA-DQ8.1 variants may be necessary but not sufficient for disease development [208, 207, 209].
Because of this, the primary value of genetic testing is to rule out celiac disease/gluten intolerance. If you are among the 60% of people who do not carry either of these variants, you are unlikely (>95%) to be at risk. That means that you can avoid unnecessary invasive test procedures, such as blood punctures, duodenal biopsies, etc. .
Apart from celiac disease, studies suggest that having either HLA-DQ2 or HLA-DQ8 is associated with an increased risk of type 1 diabetes, with a higher risk for people who carry both variants [210, 211].
Myosin IXb (MYO9B) is a protein that helps maintain the intestinal barrier. Based on a study in 1.6k Europeans, these MYO9B variants have been associated with increased intestinal permeability :
Three of these variants have also been associated with IBD: rs1545620, rs1457092, and rs2305764, based on a meta-analysis of 10 studies with 8.9k cases, and 9.4k controls .
The rs1545620 and rs2305764 variants have been associated with celiac disease in multiple studies [214, 215, 216, 217]. However, there is also a study that failed to find an association between MYO9B and celiac disease .
NOD2 (also known as CARD15) functions as an “intestinal gatekeeper.” This protein recognizes bacteria, viruses, and parasites, and activates the immune system. It also helps shape our gut microbiota .
Based on one study that involved people with Crohn’s disease, their relatives, and healthy controls, these NOD2/CARD15 variants were more often found in people with Crohn’s disease and their relatives :
The same study showed that in healthy relatives of Crohn’s disease patients, 40% of those with the 3020insC and 75% of those with both 3020insC and R702W had increased intestinal permeability .
3020insC (either rs2066847 or rs5743293) was also associated with increased permeability in another study with Crohn’s disease patients .
IBD patients carrying the JAK2 rs10758669 (C) variant more often had increased intestinal permeability, based on a study in 464 Crohn’s disease patients, 292 ulcerative colitis patients, and 508 controls .
Therefore, people with Hp2 variants may have an increased risk of immune and inflammatory disorders due to higher zonulin and increased intestinal permeability .
MAGI2, MAGI3, and PARD3 are tight junction proteins.
IBD has been associated with rs6962966 in MAGI2 and rs1343126 in MAGI3 .
AHR (aryl hydrocarbon receptor) is a protein that activates detoxification enzymes in response to pollutants and cancer-causing agents. It also plays an important role in activating the immune system [229, 230].
A study suggests that AHR rs7796976 (G) may increase the risk of disturbed intestinal permeability in Crohn’s disease patients. Smoking can exacerbate this effect .