“Leaky gut” is gaining more attention by the day, although it is not a recognized medical condition. Increased intestinal permeability, also known as ‘leaky gut,’ has been linked to autoimmune diseases, chronic fatigue syndrome, allergies, and even depression. Read on to learn more about what causes the gut to get “leaky” and what conditions and diseases are linked to it.
What is the Intestinal Barrier?
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 [1].
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 [1].
The intestinal/gut barrier is amazing! It [2]:
- 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 [1]:
- Mucus
- Beneficial gut bacteria
- Antimicrobial molecules
- Immunoglobulins (especially IgA)
- Cytokines
Studies have found that gut bacteria, in particular, have many beneficial roles in maintaining the intestinal barrier. They [1]:
- Help with the digestion and absorption of nutrients
- Prevent colonization by harmful bacteria
- Stimulate immunity
What Is Leaky Gut?
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” [1].
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 [1].
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].
Leaky Gut Signs and Symptoms
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:
- Bloating
- Gas
- Cramps
- Food sensitivity
- Pain
- IBD
- IBS
- 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.
Testing for Intestinal Permeability
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.
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. Levels of lactulose vs. mannitol can then be measured in the urine [2].
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 [6].
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 [2].
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 Blood Test
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.
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.
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.
What Can Increase Gut Permeability?
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!
1) Poor Diet
Animal studies have found that unhealthy diets can create an imbalance in the intestinal barrier. These diets include:
- Diets low in fiber [1]
- Diets high in saturated fats [1]
- Diets high in fats and sugars (a typical Western diet) [2]
- Diets high in processed food containing emulsifiers [7]
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) [8].
In mice, a high-fat diet increased gut permeability by reducing the production of tight junction proteins [9].
2) Lectins
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 [10].
Animal studies suggest that when lectins cause leaky gut, both dietary and bacterial antigens (inflammatory agents) may leak into the blood and activate the immune system [11, 12, 13, 10].
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 [14].
3) Chronic Stress
Research suggests that stress hormones from the HPA axis, such as CRH, can increase intestinal permeability and cause inflammation [15, 16].
A study in 23 healthy volunteers, showed that stress from giving a public speech, measured as an increase in the stress hormone cortisol, increased gut permeability (via CRH) [17].
Maternal separation and other types of stress increase intestinal permeability in rats [18, 19].
In addition, rats who experienced maternal separation in youth are also more prone to leaky gut when they experience social stress as adults [20]!
4) Injury
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 [21].
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 [21].
Similarly, studies show that burn injuries increase intestinal permeability in both animals and humans [22].
In an animal study, mice with burn injuries had disturbed microbiota (particularly a deficiency of butyrate-producing bacteria) and increased gut permeability [23].
Research suggests that mice and rats with traumatic brain injuries also have increased intestinal permeability [24, 25].
5) Strenuous Exercise
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% [26].
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 [27].
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 [28].
Cycling at 70% capacity increased gut leakiness and the number of allergens reaching the bloodstream in another study with 10 people [29].
Two studies with 37 and 38 soldiers, respectively, suggest that high-intensity combat training increases gut permeability as well as the incidence and severity of gut-related symptoms [30, 31].
However, a study in 11 well-trained athletes showed that the gut adapted to exercise. As a result, the intestinal permeability was not affected [32].
This suggests the gut barrier may be ‘trained’ akin to training your muscles.
6) Alcohol
Alcohol may disrupt intestinal barrier function and increase gut permeability [33].
A study in 36 alcoholics suggests that alcoholics have higher gut permeability, which can persist for up to 2 weeks after drinking [34].
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) [35].
Some harmful bacteria, including E. coli, produce alcohol. Certain scientists propose that alcohol may be how these bacteria compromise the gut barrier function [36].
7) Bacterial Imbalance (Dysbiosis)
The intestinal barrier acts as a shield that may be modified by gut bacteria [37].
Research suggests that disturbances in the gut microbiota may cause gut barrier dysfunction in various disorders and diseases [37].
In a study of 100 overweight pregnant women, those with leaky gut (higher zonulin) had a lower diversity of gut bacteria [8].
At this point, however, this is all based on association and speculations.
8) Infections
Some harmful bacteria may gain access to the body by altering tight junctions to increase gut permeability [38].
In cell and animal studies, H. pylori directly increase gut permeability by acting on tight junction proteins [39, 40].
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) [41].
- Tapeworm parasites can caused leaky gut in rats [42].
- Candida increased gut permeability in a cell-based study [43].
9) Inflammation
Molecular studies have shown that inflammation may increase intestinal permeability through TNF-alpha, IL-1beta, IFN-gamma, Nf-KB, and other cytokines [44, 45, 46, 47].
10) Drugs, Including NSAIDs
Conventional NSAIDs increase gut permeability in humans within 24 hours of ingestion. This is more evident when these drugs are taken long-term [48, 49, 50, 51, 52].
Stomach acid-suppressing drugs (PPI) may also increase gut permeability based on studies in people with liver cirrhosis [53]. However, there are also studies that show the exact opposite. In 14 patients with cystic fibrosis, PPIs seemed to reduce gut permeability [54].
11) Some Supplements
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 [55].
However, we don’t know how long-lasting or meaningful this effect is.
Similarly, a study of 153 children showed that iron supplementation can increase intestinal permeability (lactulose-mannitol test) [56].
12) Nutrient Deficiencies
Molecular, cell, and animal studies suggest that zinc plays an important role in maintaining the intestinal barrier [57, 58, 59].
A study in 25 children has found that perturbed zinc balance may be associated with abnormal gut permeability (measured by a lactulose-mannitol test) [60].
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 [61].
- 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.
13) Circadian Rhythm Disturbances
Circadian rhythms may be important for the maintenance of the intestinal barrier [65].
An observational study of 22 workers showed that night-shift workers were more prone to alcohol-induced leaky gut compared to day-shift workers [66].
Circadian disruptions, by either genetics or environmental cues, caused leaky gut in mice. These mice were also more susceptible to further gut damage by alcohol [65, 67].
14) Radiation
Exposure to radiation, such as radiation therapy, increases intestinal permeability in humans [68, 69].
In animal studies, radiation rapidly disrupted tight junctions in mice and increased gut permeability in monkeys [70, 71].
15) Chemotherapy
Chemotherapy increases intestinal permeability in humans; however, the exact mechanism is still not fully understood [72, 73, 74, 75].
16) Birth and Infancy
Studies suggest that babies may naturally have a more leaky gut, which allows them to absorb immune substances from their mother’s milk [76].
In addition, research shows that preterm babies have a more leaky gut than full-term babies during the first 2 days of life [76, 77].
17) Formula vs. Breastfeeding
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) [78].
18) Aging
The intestinal barrier may weaken as we age. Research suggests that gut permeability (measured by zonulin) is higher in older people [79].
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 [80].
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 [79].
Diseases Linked to Leaky Gut
1) Autoimmune Diseases
There are scientists who suggest that a dysfunctional intestinal barrier may be an important cause of autoimmune disorders [1].
They further think that leaky gut may be a source of the whole-body immune activation and Th17/Treg cell imbalance seen in autoimmune diseases [81].
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 [91]
- Lupus [92]
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 [93].
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 [1].
Research suggests that blocking zonulin, a protein that opens tight junctions may help reduce intestinal permeability. It was able to reverse type 1 diabetes in a study with rats [4, 94].
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 [95].
2) Inflammatory Bowel Disease (IBD)
Research suggests that people who have inflammatory bowel disease (Crohn’s disease or ulcerative colitis) may have a disrupted intestinal barrier [96, 97].
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 [98].
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) [99].
According to a similar study, the ‘gut leakiness’ in patients with Crohn’s disease and their relatives could be further exacerbated by aspirin [100].
A therapy that blocks TNF-alpha, an inflammation-promoting cytokine, restored intestinal permeability in a study with 23 Crohn’s disease patients [101].
3) Irritable Bowel Syndrome (IBS)
Patients with IBS may also have increased gut permeability [102, 103].
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 [104].
4) Chronic Fatigue Syndrome
Some scientists suggest that Increased gut permeability may be behind the severe fatigue and brain fog in patients with chronic fatigue syndrome [81, 105].
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) [105].
5) Diseases of the Nervous System
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 [111]
- Parkinson’s disease [112]
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.
6) Depression
A study of 112 people with depression (and 28 controls) showed they depressed people had more antibodies against gut bacteria, suggesting a ‘leaky gut’ [113, 114].
A study of 60 alcoholic subjects found that those who had leaky gut were more prone to depression and anxiety [115].
7) Autism
Some studies (53 patients and 73 controls) showed that intestinal permeability was higher in those with autism [116, 117].
Another study found that both those with autism and their first-degree relatives were more likely to have higher intestinal permeability [118].
However, 2 other studies (140 subjects) found no abnormal intestinal permeability in autistic children [119, 120].
8) Allergies
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 [121].
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 [124].
9) Asthma
Studies suggest that gut permeability may be higher in people with both allergic and nonallergic asthma [125, 126, 127].
10) Eczema, Psoriasis, and Acne
Some scientists think that increased intestinal permeability may be one of the reasons people experience trouble with acne [128, 129]. More evidence is needed, however, to validate this theory.
In a small study of 15 people, those with psoriasis showed higher intestinal permeability than controls [130].
In another study compromised intestinal barrier was found in 18 people with eczema [131].
11) Obesity
Obese people may 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 [132, 133].
Higher gut permeability was associated with higher BMI, increased inflammation (IL-6), and lower insulin sensitivity in 123 men [134].
12) Diabetes
Leaky gut has been associated with type 2 diabetes in a study that compared 130 people with diabetes and 161 controls [135].
Similarly, another study found a link between increased gut permeability (high zonulin)and pregnancy-induced diabetes in 88 pregnant women [136].
13) Liver Disease
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 [137].
Research further suggests that patients with liver cirrhosis may also have increased intestinal permeability and intestinal barrier dysfunction [138].
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 [139].
14) Obstructive Sleep Apnea
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 [140].
15) Cancer
A couple of studies suggest that humans with cancer may have increased intestinal permeability [141, 142].
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 [143].
Further Reading
Takeaway
“Leaky gut syndrome” is the controversial name given to a condition in which the barrier between the intestine and the bloodstream is “leaky” and allows potentially harmful compounds to cross. The most common signs and symptoms of this condition include bloating, gas, cramps, and pain.
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.
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.
