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20 Causes of Leaky Gut Syndrome & 15 Healing Treatments

Written by Biljana Novkovic, PhD | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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‘Leaky gut’ is gaining more attention by the day. This is because various diseases are increasingly associated with the state of our gut. Increased intestinal permeability, also known as ‘leaky gut,’ can trigger autoimmune diseases, chronic fatigue syndrome, allergies, and even depression. In this post, you will learn more about the intestinal barrier, factors that disrupt it, and ways in which you can heal a leaky gut.

What is the Intestinal Barrier?

Source: http://www.nature.com/ctg/journal/v7/n10/fig_tab/ctg201654f1.html#figure-title

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 [1].

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 [1].

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 [2].

Many other factors help support this barrier [1]:

  • Mucus
  • Beneficial gut bacteria
  • Antimicrobial molecules
  • Immunoglobulins (especially IgA)
  • Cytokines

Gut bacteria, in particular, have many beneficial roles in maintaining the intestinal barrier [1]:

  • 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” [1].

When the gut is leaky, gut bacteria and their products can escape the gut, which can produce inflammation and cause tissue damage [1].

Also, food-derived antigens (proteins or partially digested proteins) can pass through the gut and promote both local or whole-body immune responses [1].

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:

  • Bloating
  • Gas
  • Cramps
  • Food sensitivity
  • Pain
  • IBD
  • IBS
  • 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 [5].

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 [2].

Levels of lactulose vs. mannitol can then be measured in the urine [2].

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 [2].

Zonulin Blood Test

Zonulin is a protein that causes tight junctions to open. More zonulin means higher intestinal permeability.

It is a good marker for leaky gut and autoimmune diseases that are caused by the zonulin pathway [3, 4].

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 [1]
  • Diets high in saturated fats [1]
  • Diets high in fats and sugars (a typical Western diet) [2]
  • Processed food containing emulsifiers [6]

For example, pregnant women who ate more healthily (more omega-3 fatty acids, fiber, vitamins, and minerals) had a lower intestinal permeability (measured by zonulin) [7].

A high-fat diet increases gut permeability by reducing tight junction protein production in mice [8].

2) Lectins

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586524/

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 [9].

When lectins cause leaky gut, both dietary and bacterial antigens (inflammatory agents) leak into the blood and activate the immune system [10, 11, 12, 9].

Some dietary sources of lectins, such as wheat, can directly open tight junctions in gut cells (by increasing zonulin) [13].

3) Chronic Stress

Stress hormones from the HPA axis, such as CRH, can increase intestinal permeability and cause inflammation [14, 15].

In 23 healthy volunteers, stress from giving a public speech increased gut permeability (via CRH) in those who also had increased cortisol [16].

Maternal separation and other types of stress increase intestinal permeability in rats [17, 18].

Rats who experienced maternal separation in youth are also more prone to the leaky gut when they experience social stress as adults [19].

4) Injury

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 [20].

Also, intensive care patients with a large increase in intestinal permeability are at more risk of whole-body inflammation, multiple organ dysfunction, and infections [20].

Burn injuries caused leaky gut in both animals and humans [21].

Mice with burn injuries had disturbed microbiota (particularly a deficiency of butyrate-producing bacteria) and increased gut permeability [22].

Mice and rats with traumatic brain injuries also had increased intestinal permeability [23, 24].

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% [25].

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 [26].

Running at 70% capacity increased intestinal permeability in 20 athletes, which is more pronounced in those who also already suffer from gut-related symptoms [27].

Cycling at 70% capacity increased gut leakiness and the number of allergens reaching the bloodstream in 10 people [28].

Soldiers in high-intensity combat training had increased gut permeability as well as the incidence and severity of gut-related symptoms [29, 30].

However, in 11 well-trained athletes, the gut adapted to exercise. As a result, the intestinal permeability was not affected [31].

This suggests your gut barrier can be ‘trained’ as well as your muscles.

6) Alcohol

Alcohol can disrupt intestinal barrier function and increase gut permeability [32].

Alcoholics have higher gut permeability up to 4 days after drinking, sometimes even for up to 2 weeks [33].

One week of moderate consumption of red wine is safe in healthy people. However, it increased intestinal permeability in 14 patients with inactive IBD [34].

Some harmful bacteria, including E. coli, produce alcohol, which may be how these bacteria compromise the gut barrier function [35].

7) Bacterial Imbalance (Dysbiosis)

The intestinal barrier acts as a shield that can be modified by gut bacteria [36].

Disturbances in the gut microbiota cause gut barrier dysfunction in various disorders and diseases [36].

A study of 100 overweight pregnant women showed that those with leaky gut (high zonulin) had a lower diversity of gut bacteria [7].

8) Infections

Many harmful bacteria gain access to the body by altering tight junctions to increase gut permeability [37].

  • H. pylori directly increase gut permeability by acting on tight junction proteins [38, 39].

Other types of infections also increase intestinal permeability. For example:

  • Patients with malaria have increased intestinal permeability [40].
  • Tapeworm parasites caused leaky gut in rats [41].
  • Candida increased gut permeability (cell-based study) [42].

9) Inflammation

Inflammation increases intestinal permeability through TNF-alpha, IL-1beta, IFN-gamma, Nf-KB, and other cytokines [43, 44, 45, 46].

10) Drugs, Including NSAIDs and PPIs

Conventional NSAIDs increase gut permeability within 24 hours of ingestion. This is especially evident when they are taken long-term [47, 48, 49, 50, 51].

Stomach acid-suppressing drugs (PPI) also increase gut permeability [52, 53].

However, in patients with cystic fibrosis, PPIs seem to reduce gut permeability [54].

11) Zinc Deficiency

Zinc plays an important role in maintaining the intestinal barrier [55, 56, 57].

Perturbed zinc balance is associated with abnormal gut permeability in children [58].

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 [59]
  • 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 [63].

14) Iron

A study of 153 children showed that iron supplementation increased intestinal permeability [64].

15) Circadian Rhythm Disturbances

Circadian rhythms are important for the maintenance of the intestinal barrier [65].

A study of 22-night workers showed that they are more prone to alcohol-induced leaky gut [66].

Circadian disruptions, by either genetics or environmental cues, caused gut leakiness in mice. These mice were also more susceptible to further gut damage by alcohol [65, 67].

16) Radiation

Exposure to radiation, such as in radiation therapy, increases intestinal permeability in humans [68, 69].

Radiation rapidly disrupted tight junctions in mice and increased gut permeability in monkeys [70, 71].

17) Chemotherapy

Chemotherapy increases intestinal permeability; however, the exact mechanism is still not fully understood [72, 73, 74, 75].

18) Birth and Infancy

Babies naturally have a more leaky gut, which allows them to absorb immune substances from the mother’s milk [76].

Preterm babies have a more leaky gut than full-term during the first 2 days of life [76, 77].

19) Formula vs. Breastfeeding

Infants fed with formula had a more leaky gut than breastfed infants [78].

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%) [79].

20) Aging

The intestinal barrier may weaken as we age. Gut permeability (measured by zonulin) is higher in older people [80].

In 18 elderly people, high gut permeability was associated with higher TNF-alpha and IL-6. It was also associated with lower muscle strength and less habitual physical activity [80].

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 [81].

Diseases Linked to Leaky Gut

1) Autoimmune Diseases

A dysfunctional intestinal barrier is an important cause of autoimmune disorders [1].

Leaky gut can be a source of the whole-body immune activation and Th17/Treg cell imbalance seen in autoimmune diseases [82].

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 [92]
  • Lupus [93]

Less than 10% of the people who are genetically susceptible to autoimmune disease, actually develop the diseases [94].

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 [1].

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 [97].

2) IBD

IBD patients have a disrupted intestinal barrier [98, 99].

In 110 patients with IBD, impaired intestinal permeability was associated with ongoing bowel symptoms. Increases in permeability correlated with more severe diarrhea [100].

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) [101].

The ‘gut leakiness’ in Crohn’s patients and their relatives can be further greatly increased by aspirin [102].

A therapy that blocks TNF-alpha, an inflammation-promoting cytokine, restored intestinal permeability in 23 Crohn’s disease patients [103].

3) IBS

Patients with IBS have increased gut permeability [104, 105].

When 36 IBS patients with suspected food intolerance ate the food in question, it immediately disrupted their intestinal barrier, as compared to controls [106].

4) Chronic Fatigue Syndrome

Increased gut permeability is also a likely cause of the severe fatigue and brain fog in patients with chronic fatigue syndrome [82, 107].

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) [107].

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 [113]
  • Parkinson’s disease [114]

6) Depression

A study of 112 people with depression (and 28 controls) showed they have increased antibodies against gut bacteria, suggesting a ‘leaky gut’ [115, 116].

A study of 60 alcoholic subjects with leaky gut showed that they are more prone to depression and anxiety [117].

7) Autism

Some studies (53 patients and 73 controls) showed that intestinal permeability is higher in those with autism [118, 119].

In fact, both those with autism and their first-degree relatives are more likely to have higher intestinal permeability [120].

Patients with autism on a gluten-free, casein-free diet had lower gut permeability than those on unrestricted diets [120].

However, 2 other studies (140 subjects) found no abnormal intestinal permeability in autistic children [121, 122].

8) Allergies

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 [123].

Those with food allergies have leaky gut after eating trigger foods. However, their gut permeability was also increased at baseline, when they were on elimination diets [124, 125, 123].

A study of 131 allergic children on elimination diets with no symptoms showed that about a third had increased gut permeability [126].

9) Asthma

Gut permeability is higher in people with both allergic and nonallergic asthma [127, 128].

Another study on 14 patients with moderate to severe asthma showed that half had abnormal intestinal permeability [129].

10) Eczema, Psoriasis, and Acne

Increased intestinal permeability may be one reason for trouble with acne [130, 131].

A study of 15 patients with psoriasis showed higher intestinal permeability than controls [132].

A study of 18 people with eczema revealed a compromised intestinal barrier regardless if they had food allergies or not [133].

11) Obesity

Obese people have leaky guts. Two studies, one with 40 and one with 55 subjects, showed that those with larger waists and worse metabolic parameters had higher gut permeability [134, 135].

Higher gut permeability is associated with higher BMI, increased inflammation (IL-6), and lower insulin sensitivity (123 men) [136].

12) Diabetes

Leaky gut is a risk factor for type 2 diabetes (130 people with diabetes and 161 controls) [137].

Increased gut permeability (high zonulin) is associated with pregnancy-induced diabetes (88 pregnant women) [138].

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) [139].

Patients with liver cirrhosis have increased intestinal permeability and intestinal barrier dysfunction [140].

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 [141].

14) Obstructive Sleep Apnea

Patients with obstructive sleep apnea have a higher risk of having leaky gut (38 patients and 38 controls) [142].

15) Cancer

Patients with acute myeloid leukemia (16 patients) and patients with breast cancer (10 patients and 22 controls) had increased intestinal permeability [143, 144].

Increased tight junction permeability precedes the development of colon cancer in rats [145].

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 [146].

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 [2].

1) Lectin Avoidance Diet

Lectins can cause leaky gut. The leaky gut then allows more of the dietary and bacterial antigens (inflammatory agents) to come in contact with the immune system [10, 147].

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.

You can read more about lectins and lectin avoidance diet here.

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 [148].

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 [149].

DHA, a long-chain omega-3 fatty acid, improved barrier function in mice with gut inflammation [150].

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 [151].

Yogurt with probiotics prevented the disruption of the intestinal barrier in rats with gut inflammation [152].

Fermented barley and soybean prevented gut barrier dysfunction in mice with IBD-like gut inflammation by increasing tight junction proteins [153].

Fermented soy germ extract also decreased gut permeability in rats with IBD-like inflammation [154].

Finally, kimchi-derived bacteria increased tight junction protein levels in mice [155].

Broccoli Sprouts

Broccoli sprouts protect the intestinal barrier (tested on human cells) [156].

Sulforaphane, found in high amounts in broccoli sprouts, strengthened the gut barrier in mice [157].

3) Stress Management

Much of the emerging research shows that stress increases intestinal permeability [14, 15, 16].

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 [65].

5) Avoid Alcohol

Alcohol increases intestinal permeability and is best avoided [32, 33, 34].

Even moderate consumption can increase intestinal permeability in susceptible people [158].

6) Moderate Exercise

Non-impact exercise, such as swimming, can be beneficial in moderation.

Swimming increased tight junction protein levels in rats [159].

In mice, 30 minutes of swimming per day maintained low intestinal permeability. It also prevented chronic stress-induced gut barrier dysfunction [160].

7) Avoid Medications That Cause Leaky Gut

Whenever possible, avoid NSAIDs and proton pump inhibitors [52, 53].

These increase intestinal permeability [49, 50, 51].

Tylenol, on the other hand, may even decrease intestinal permeability by increasing tight junction proteins in gut cells [161].

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

Vitamin A lowered intestinal permeability in deficient children (DB-RCT, 79 children) [162].

Vitamin D

Vitamin D maintains the intestinal barrier and, in fact, has been recognized as an intestinal permeability protector [62, 163, 1].

Vitamin D maintained low intestinal permeability in Crohn’s disease patients (DB-RCT, 27 patients) [164].

Vitamin D reduced the sensitivity of the intestinal barrier to alcohol in mice [165].

Vitamin B

Niacin (vitamin B3) decreased intestinal permeability in patients with alcohol-induced niacin deficiency [166].


Zinc restored intestinal permeability in Crohn’s disease patients, probably by maintaining tight junctions [167, 168].

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 [167].

Low levels of zinc improved intestinal permeability in children with diarrhea (DB-RCT, 58 subjects) [169].

9) Supplements


Glutamine is an important nutrient that helps maintain intestinal barrier function [170].

Depletion of glutamine results in a decrease of tight junction proteins and an increase in intestinal permeability [170].

Glutamine had beneficial effects on intestinal integrity in 101 preterm infants and increased intestinal barrier function in 80 malnourished children [171, 172].

A study of 51 cancer patients showed that glutamine reduced the chemotherapy-induced increase in intestinal permeability [173].

Glutamine reduced radiation-caused gut injury and maintained gut permeability in rats [174].


Quercetin improves the function of the gut barrier by increasing the assembly of tight junction proteins [175, 176].

Myricetin and kaempferol, which are similar flavonoids to quercetin, also improved intestinal barrier function in cell-based studies [177].

Quercetin protected the intestinal barrier from NSAID-induced damage in rats [178, 179].

These flavonoids are naturally found in fruits, vegetables, nuts, berries, and teas, but are also available as supplements.


Melatonin helps heal the gut barrier.

Melatonin markedly improved gut barrier functions in rats, where the barrier was previously weakened by alcohol or diabetes [180, 181, 182].

Melatonin reduced elevated gut permeability in mice with IBD-like gut inflammation and in mice treated with NSAIDs [183, 184].

Alcoholics have lower blood melatonin, which correlates with increased intestinal permeability (20 alcoholics and 17 controls) [185].

Lipoic Acid

Lipoic acid supplementation reduced intestinal permeability in post-weaning rats [186].


Ginkgo biloba helped heal the gut barrier in rats by restoring tight junctions [187].


In rats, curcumin restored intestinal permeability by increasing tight junction proteins [188].

Curcumin helped with NSAID-induced increases in gut permeability in rats [189].

Given with antibiotics, curcumin improved intestinal barrier function in mice fed a Western diet [190].

Curcumin also protected tight junctions and barrier function in human cells [191].

10) Probiotics

Probiotics help reduce gut leakiness. They strengthen tight junctions and restore the integrity of the intestinal barrier.

Plantarum promoted gut barrier repair and increased the stability of tight junctions (10 and 7 healthy subjects, respectively) [192, 193].

Fermented milk with probiotics decreased gut permeability in patients with IBS (DB-RCT, 30 subjects) [194].

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 [199]
  • L. plantarum [200, 201, 202]
  • L. paracasei [203]
  • L. gasseri [204]
  • Bifidobacterium infantis [205]
  • L. helveticus and B. longum [206]
  • L. plantarum and L. reuteri [207]
  • Bacteroides fragilis (improved autism-related symptoms in mice) [208]
  • Escherichia coli Nissle 1917 [209]

11) Prebiotics

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) [210].

Prebiotic galactooligosaccharides (GOS) improved intestinal barrier function in rats with pancreatitis [211].

Prebiotics lowered intestinal permeability and improved tight-junction integrity in obese and diabetic mice [212].

12) Butyrate

Butyrate is a short-chain fatty acid produced by gut bacteria. It strengthens the gut barrier and reduces intestinal permeability [213, 214, 215, 216].

Butyrate increased tight junction proteins [217, 218, 219].

Butyrate helped protect the intestinal barrier in rats with gut inflammation, and in mice fed a high-fat diet or exposed to chemotherapy [220, 221, 222].

13) Drugs

Lubiprostone, a drug used to treat chronic constipation, may improve leaky gut in humans (28 subjects) [223].

The combination of neomycin and bacitracin reduced intestinal permeability in mice [224].

Intestinal permeability decreased after cefotaxime and vancomycin treatment in rats [225].

Tylenol may decrease intestinal permeability since it increases the levels of tight junction proteins in gut cells [161].

THC and CBD oil accelerated the recovery of inflammation-induced intestinal permeability in cells [226].

14) Reduce Inflammation

Systemic (whole-body) inflammation is associated with increased intestinal permeability [227, 228].

Addressing inflammation will help heal leaky gut.

15) Address chronic infections

Chronic infections can increase gut permeability, and are best dealt with if possible [38, 39, 40, 41, 42].

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 [229].

In 98% of people with celiac disease, they have either of these genes or both [230, 231].

You have HLA-DQ2.5 if you have the following variants:

  • The HLA-DQA1*0501 variant in the HLA-DQA1 gene
  • The HLA-DQB1*0201 variant in the HLA-DQB1 gene

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. [233].

Apart from celiac disease, having either HLA-DQ2 or HLA-DQ8 increases the risk of type 1 diabetes. Having both of these variants increases the risk even further [234, 235].

Women with a history of recurrent pregnancy losses are more often carriers of HLA-DQ2 and DQ8 variants (97 patients and 55 controls) [229].


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) [236]:

Three of these variants are associated with IBD: rs1545620, rs1457092, and rs2305764 (meta-analysis; 10 studies, 8,975 cases, and 9,482 controls) [237].

The rs1545620 and rs2305764 variants are also associated with celiac disease (2,717 IBD patients and 4,440 controls and 3,463 patients and 686 controls) [238, 239].

The association of MYO9B variants with celiac disease was confirmed in other studies [240, 241].

However, some also failed to find an association (415 CD patients and 433 controls) [242].

rs2279003 and rs2305764 may increase the risk of type 1 diabetes (316 patients and 706 controls) [243].

rs1457092 was associated with lupus and rheumatoid arthritis (349 lupus patients, 356 arthritis patients, and 345 healthy controls) [240].


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 [244].

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) [245]:

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 [245].

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) [246].


Janus kinase-2 (JAK2) promotes the growth and division of cells, in response to hormones and cytokines (interferon, erythropoietin, leptin, and growth hormone) [247].

IBD patients carrying the JAK2 rs10758669 (C) variant more often have increased intestinal permeability (464 Crohn’s disease patients, 292 ulcerative colitis patients, 508 controls) [248].


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.

It was discovered that prehaptoglobin-2, a precursor of the Hp2 variant, is actually zonulin [249, 250].

Therefore, people with Hp2 variants may have an increased risk of immune and inflammatory disorders due to higher zonulin and increased intestinal permeability [249].


MAGI2, MAGI3, and PARD3 are tight junction proteins.

IBD is associated with rs6962966 in MAGI2 and rs1343126 in MAGI3 [251].

rs10763976 in PARD3 and rs6962966 in MAGI2 are associated with both celiac disease and ulcerative colitis [252].


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) [255].

About the Author

Biljana Novkovic

Biljana received her PhD from Hokkaido University.
Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science &amp; health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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