What is the Intestinal Barrier?
The main function of the gut is to absorb nutrients from the food. However, the gut also has another important function – to keep harmful things such as bacteria (good as well as harmful), toxins, and food antigens (inflammatory agents) out and away from the rest of the body .
This 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 covers a surface of about 400 m2. It uses approximately 40% of the body’s energy expenditure and it is renewed approximately every 5 days .
Many other factors help support this barrier :
- Beneficial gut bacteria
- Antimicrobial molecules
- Immunoglobulins (especially IgA)
Gut bacteria, in particular, have many beneficial roles in maintaining the intestinal barrier :
- Helping the digestion and absorption of nutrients
- Preventing colonization by harmful bacteria
- Stimulating immunity
- Improving mood
What Is Leaky Gut?
When there are abnormalities in the intestinal barrier, the intestinal permeability increases. This means more of the gut content can pass/leak through, which is referred to as “leaky gut” .
When the gut is leaky, gut bacteria and their products can escape the gut, which can produce inflammation and cause tissue damage .
Also, food-derived antigens (proteins or partially digested proteins) can pass through the gut and promote both local or whole-body immune responses .
Zonulin is a protein that causes tight junctions to open. When tight junctions open, intestinal permeability increases. Bacteria and gluten are examples of agents that can cause ‘leaky gut’ by increasing zonulin [3, 4].
Zonulin levels may be a measure of paracellular (between cell) gut permeability.
Leaky Gut Signs and Symptoms
How do you know if you suffer from leaky gut? You will likely experience one or more of the signs and symptoms listed below:
- Food sensitivity
- Autoimmune disease
- Thyroid problems
- Skin conditions (inflammatory, acne)
Testing for Intestinal Permeability
The Lactulose-Mannitol Test
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 .
Note that decreased gut flow and kidney dysfunction can affect the results. The test is also unsuitable in patients on blood transfusion since mannitol is used in the storage solution of banked blood .
Zonulin Blood Test
Zonulin is a protein that causes tight junctions to open. More zonulin means higher intestinal permeability.
Blood tests for zonulin are now available.
Food Sensitivity or Antibodies Against Foods
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.
Causes of Leaky Gut
1) Poor Diet
Unhealthy diets can create an imbalance in the intestinal barrier. These diets include:
- Low-fiber diets 
- Diets high in saturated fats 
- Diets high in fats and sugars (a typical Western diet) 
- Processed food containing emulsifiers 
A high-fat diet increases gut permeability by reducing tight junction protein production in mice .
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, they can also bind to the surface of gut-lining cells and disturb the gut barrier .
Some dietary sources of lectins, such as wheat, can directly open tight junctions in gut cells (by increasing zonulin) .
3) Chronic Stress
Rats who experienced maternal separation in youth are also more prone to the leaky gut when they experience social stress as adults .
Twenty-nine intensive care patients showed increased intestinal permeability 72 to 96 hours after trauma. The more severe the injury, the greater the increase in gut permeability .
Also, intensive care patients with a large increase in intestinal permeability are at more risk of whole-body inflammation, multiple organ dysfunction, and infections .
Burn injuries caused leaky gut in both animals and humans .
5) Strenuous Exercise
Exercise can 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.
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% .
People who exercise at high intensities for longer periods have compromised gut barrier integrity. This puts them at a greater risk of chronic inflammation and diseases .
Running at 70% capacity increased intestinal permeability in 20 athletes, which is more pronounced in those who also already suffer from gut-related symptoms .
Cycling at 70% capacity increased gut leakiness and the number of allergens reaching the bloodstream in 10 people .
However, in 11 well-trained athletes, the gut adapted to exercise. As a result, the intestinal permeability was not affected .
This suggests your gut barrier can be ‘trained’ as well as your muscles.
Alcohol can disrupt intestinal barrier function and increase gut permeability .
Alcoholics have higher gut permeability up to 4 days after drinking, sometimes even for up to 2 weeks .
One week of moderate consumption of red wine is safe in healthy people. However, it increased intestinal permeability in 14 patients with inactive IBD .
Some harmful bacteria, including E. coli, produce alcohol, which may be how these bacteria compromise the gut barrier function .
7) Bacterial Imbalance (Dysbiosis)
The intestinal barrier acts as a shield that can be modified by gut bacteria .
A study of 100 overweight pregnant women showed that those with leaky gut (high zonulin) had a lower diversity of gut bacteria .
Many harmful bacteria gain access to the body by altering tight junctions to increase gut permeability .
Other types of infections also increase intestinal permeability. For example:
- Patients with malaria have increased intestinal permeability .
- Tapeworm parasites caused leaky gut in rats .
- Candida increased gut permeability (cell-based study) .
10) Drugs, Including NSAIDs and PPIs
However, in patients with cystic fibrosis, PPIs seem to reduce gut permeability .
11) Zinc Deficiency
Perturbed zinc balance is associated with abnormal gut permeability in children .
12) Vitamin Deficiency
Vitamins (especially A and D) are necessary for the proper function of the intestinal barrier since:
- A vitamin A-deficient diet impaired the intestinal barrier in rats 
- Vitamin D-deficient mice were more sensitive to gut barrier disruption [60, 61, 62]
13) Vitamin C
A study on 28 healthy female volunteers showed that vitamin C may increase intestinal permeability and that this effect is additive when added to aspirin .
A study of 153 children showed that iron supplementation increased intestinal permeability .
15) Circadian Rhythm Disturbances
Circadian rhythms are important for the maintenance of the intestinal barrier .
A study of 22-night workers showed that they are more prone to alcohol-induced leaky gut .
18) Birth and Infancy
Babies naturally have a more leaky gut, which allows them to absorb immune substances from the mother’s milk .
19) Formula vs. Breastfeeding
Infants fed with formula had a more leaky gut than breastfed infants .
A study on 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%) .
The intestinal barrier may weaken as we age. Gut permeability (measured by zonulin) is higher in older people .
However, a study on 215 adults suggested that the gut barrier does not deteriorate with age per se. Instead, it deteriorated due to chronic inflammation and minor diseases that get more common as we age .
Diseases Linked to Leaky Gut
1) Autoimmune Diseases
A dysfunctional intestinal barrier is an important cause of autoimmune disorders .
Increased gut permeability may favor the development of:
- Type 1 diabetes [83, 84, 85]
- Autoimmune hepatitis [86, 87]
- Ankylosing spondylitis [88, 89]
- Celiac disease [90, 91]
- Rheumatoid arthritis 
- Lupus 
Less than 10% of the people who are genetically susceptible to autoimmune disease, actually develop the diseases .
This means that environmental factors are much more important in autoimmune disease development.
In genetically predisposed people, a leaky gut allows foreign inflammatory agents to enter the body. Then, these agents trigger the initiation and development of the autoimmune disease .
Blocking zonulin, a protein that opens tight junctions can reduce intestinal permeability. It can also reverse type 1 diabetes in rats and prevent leaky gut in celiac patients exposed to gluten [4, 95, 96].
A study (DB-RCT) of 342 adults showed that larazotide, a drug that blocks zonulin, reduced signs and symptoms in celiac disease patients .
In 110 patients with IBD, impaired intestinal permeability was associated with ongoing bowel symptoms. Increases in permeability correlated with more severe diarrhea .
Intestinal permeability is increased in most patients with Crohn’s disease. However, it is also increased by 30% of their healthy relatives (223 healthy subjects) .
The ‘gut leakiness’ in Crohn’s patients and their relatives can be further greatly increased by aspirin .
A therapy that blocks TNF-alpha, an inflammation-promoting cytokine, restored intestinal permeability in 23 Crohn’s disease patients .
When 36 IBS patients with suspected food intolerance ate the food in question, it immediately disrupted their intestinal barrier, as compared to controls .
4) Chronic Fatigue Syndrome
A study of 41 patients with chronic fatigue syndrome showed improvement in more than half when they took supplements that help gut barrier function (such as glutamine and zinc) .
5) Diseases of the Nervous System
Increased gut permeability is found in the following diseases:
- Multiple sclerosis [108, 109, 110]
- Schizophrenia (those with a history of a childhood celiac disease have an increased risk of developing schizophrenia) [111, 112]
- Alzheimer’s disease 
- Parkinson’s disease 
In fact, both those with autism and their first-degree relatives are more likely to have higher intestinal permeability .
Patients with autism on a gluten-free, casein-free diet had lower gut permeability than those on unrestricted diets .
A study of 41 patients with food allergies or food sensitivities showed that they have increased gut permeability. In fact, those with higher intestinal permeability have more severe symptoms .
A study of 131 allergic children on elimination diets with no symptoms showed that about a third had increased gut permeability .
Another study on 14 patients with moderate to severe asthma showed that half had abnormal intestinal permeability .
10) Eczema, Psoriasis, and Acne
A study of 15 patients with psoriasis showed higher intestinal permeability than controls .
A study of 18 people with eczema revealed a compromised intestinal barrier regardless if they had food allergies or not .
Higher gut permeability is associated with higher BMI, increased inflammation (IL-6), and lower insulin sensitivity (123 men) .
Leaky gut is a risk factor for type 2 diabetes (130 people with diabetes and 161 controls) .
Increased gut permeability (high zonulin) is associated with pregnancy-induced diabetes (88 pregnant women) .
13) Liver Disease
Intestinal permeability is increased in children with fatty liver. Those with higher permeability have more severe disease symptoms (39 patients and 21 controls) .
Patients with liver cirrhosis have increased intestinal permeability and intestinal barrier dysfunction .
Not all heavy drinkers develop a chronic liver injury. A leaky gut may be a necessary factor for the development of chronic liver injury among heavy drinkers .
14) Obstructive Sleep Apnea
Patients with obstructive sleep apnea have a higher risk of having leaky gut (38 patients and 38 controls) .
Increased tight junction permeability precedes the development of colon cancer in rats .
In cancer-prone mice, a high-fat diet disrupted gap junction proteins, thereby increasing gut permeability. This led to increased inflammation and development of tumors .
How to Heal a Leaky Gut
You can avoid and repair leaky gut by making lifestyle modifications. This means avoiding triggers like gluten, alcohol, NSAIDs, stress, and intense physical activity .
1) Lectin Avoidance Diet
If you feel you are lectin sensitive, it is best to avoid lectin-rich foods and any other food you are sensitive to.
This means you should eliminate sugars, starches, grains, and other irritating foods.
2) Beneficial Foods
Unsaturated Fat (Omega-3)
It is important to maintain a healthy balance of unsaturated vs. saturated fats, but also omega-3 vs. omega-6 fatty acids.
Western diets typically have an excess of omega-6 and not enough omega-3 fatty acids.
Mice on a high omega-6 diet developed abnormal gut permeability and chronic low-grade inflammation .
On the other hand, mice that received more omega-3 fatty acids had decreased intestinal permeability. Their gut lining also sustained less damage in chemotherapy .
Fermented Dairy and Vegetables
Fermented dairy and vegetables are excellent sources of beneficial bacteria. These include yogurt, kefir, sauerkraut, and kimchi.
Yogurt improves intestinal barrier by increasing tight junctions .
Fermented barley and soybean prevented gut barrier dysfunction in mice with IBD-like gut inflammation by increasing tight junction proteins .
Fermented soy germ extract also decreased gut permeability in rats with IBD-like inflammation .
Finally, kimchi-derived bacteria increased tight junction protein levels in mice .
Broccoli sprouts protect the intestinal barrier (tested on human cells) .
Sulforaphane, found in high amounts in broccoli sprouts, strengthened the gut barrier in mice .
3) Stress Management
Managing stress levels is a great way to improve the function of your intestinal barrier and your overall health.
4) Healthy Circadian Rhythm
A healthy circadian rhythm will also help keep your gut healthy .
5) Avoid Alcohol
Even moderate consumption can increase intestinal permeability in susceptible people .
6) Moderate Exercise
Non-impact exercise, such as swimming, can be beneficial in moderation.
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 .
7) Avoid Medications That Cause Leaky Gut
Tylenol, on the other hand, may even decrease intestinal permeability by increasing tight junction proteins in gut cells .
8) Vitamins and Minerals
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, iron, and B vitamins.
Vitamin A lowered intestinal permeability in deficient children (DB-RCT, 79 children) .
Vitamin D maintained low intestinal permeability in Crohn’s disease patients (DB-RCT, 27 patients) .
Vitamin D 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 children with diarrhea (DB-RCT, 58 subjects) .
Glutamine is an important nutrient that helps maintain intestinal barrier function .
Depletion of glutamine results in a decrease of tight junction proteins and an increase in intestinal permeability .
A study of 51 cancer patients showed that glutamine reduced the chemotherapy-induced increase in intestinal permeability .
Glutamine reduced radiation-caused gut injury and maintained gut permeability in rats .
Myricetin and kaempferol, which are similar flavonoids to quercetin, also improved intestinal barrier function in cell-based studies .
These flavonoids are naturally found in fruits, vegetables, nuts, berries, and teas, but are also available as supplements.
Melatonin helps heal the gut barrier.
Alcoholics have lower blood melatonin, which correlates with increased intestinal permeability (20 alcoholics and 17 controls) .
Lipoic acid supplementation reduced intestinal permeability in post-weaning rats .
Ginkgo biloba helped heal the gut barrier in rats by restoring tight junctions .
In rats, curcumin restored intestinal permeability by increasing tight junction proteins .
Curcumin helped with NSAID-induced increases in gut permeability in rats .
Given with antibiotics, curcumin improved intestinal barrier function in mice fed a Western diet .
Curcumin also protected tight junctions and barrier function in human cells .
Probiotics help reduce gut leakiness. They strengthen tight junctions and restore the integrity of the intestinal barrier.
Fermented milk with probiotics decreased gut permeability in patients with IBS (DB-RCT, 30 subjects) .
The probiotics included S. thermophilus, L. bulgaricus, L. acidophilus, and B. longum.
The following probiotics have helped heal ‘leaky gut’ in animal and cell studies:
- Lactobacillus rhamnosus GG [195, 196, 197, 198]
- L. acidophilus and Streptococcus thermophilus 
- L. plantarum [200, 201, 202]
- 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.
Inulin-enriched pasta preserved the intestinal barrier and decreased zonulin (20 healthy volunteers) .
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 .
Lubiprostone, a drug used to treat chronic constipation, may improve leaky gut in humans (28 subjects) .
The combination of neomycin and bacitracin reduced intestinal permeability in mice .
Intestinal permeability decreased after cefotaxime and vancomycin treatment in rats .
Tylenol may decrease intestinal permeability since it increases the levels of tight junction proteins in gut cells .
14) Reduce Inflammation
Addressing inflammation will help heal leaky gut.
15) Address chronic infections
Genetic Factors That Influence Intestinal Permeability
HLA-DQ2.5 and HLA-DQ8.1
HLA-DQ is a protein found on the surface of cells that communicate with the immune system (it presents antigens to immune cells).
Two variants, HLA-DQ2.5 and HLA-DQ8.1 increase the risk of celiac disease by about 6-fold .
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
Up to 40% of the general population has these variants. However, only about 1% develop celiac disease. This indicates that HLA-DQ2.5 and -DQ8.1 variants are necessary but not sufficient for disease development [232, 231, 233].
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 likely (>95%) to not be at risk. That means that you can avoid unnecessary invasive test procedures, such as blood punctures, duodenal biopsies, etc. .
Women with a history of recurrent pregnancy losses are more often carriers of HLA-DQ2 and DQ8 variants (97 patients and 55 controls) .
Myosin IXb (MYO9B) is a protein that helps maintain the intestinal barrier. These MYO9B variants may increase intestinal permeability (a study of 1,614 Europeans) :
Three of these variants are associated with IBD: rs1545620, rs1457092, and rs2305764 (meta-analysis; 10 studies, 8,975 cases, and 9,482 controls) .
However, some also failed to find an association (415 CD patients and 433 controls) .
rs2279003 and rs2305764 may increase the risk of type 1 diabetes (316 patients and 706 controls) .
rs1457092 was associated with lupus and rheumatoid arthritis (349 lupus patients, 356 arthritis patients, and 345 healthy controls) .
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 .
These NOD2/CARD15 variants are more often found in people with Crohn’s disease and their relatives (128 patients with Crohn’s disease, 129 first-degree relatives, 66 non-related household members, and 96 healthy controls) :
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 associated with increased permeability in 75% of multiplex and 61% of the sporadic Crohn’s disease patients (115 patients, 127 first-degree relatives including some with sporadic disease, 19 healthy controls) .
HP is the haptoglobin gene. Haptoglobin binds free hemoglobin in the blood and prevents it from causing oxidative stress and tissue damage. It comes in 2 common variants: Hp1 and Hp2.
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
MAGI2, MAGI3, and PARD3 are tight junction proteins.
IBD is 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 [253, 254].
AHR rs7796976 (G) increases the risk for disturbed intestinal permeability in Crohn’s disease patients. Smoking can exacerbate this effect (28 IBD patients, 4 controls) .