The gut barrier

A layer of cells thinner than a hair separates the gut contents from the body. What keeps it tight.

How solid is the research? Promising

Increased permeability is well documented in coeliac disease and inflammatory bowel disease. As an independent cause of many other complaints (“leaky gut”) it is not proven, and there is no reliable routine test.

Cause or consequence? Cause and consequence

The leaky barrier sits at the centre of many problems: it results from overgrowth, stress and a lack of butyrate, among other things, and keeps inflammation going. That it also triggers allergies and skin problems is a widespread assumption and almost a principle in functional medicine. In humans, a disturbed barrier is so far well established mainly in coeliac disease and inflammatory bowel disease.

Healthy state

The gut lining consists of a single layer of cells. It has to manage two opposite things at once: let nutrients, water and salts through, but keep bacteria, toxins and undigested food components out. Between the cells sit protein connections, the so-called Tight junctions Protein connections that hold the cells of the gut wall tightly together. They determine what can pass between the cells. (made of proteins such as claudins, occludin and ZO-1). You can picture them as zippers that open a little as needed. Small particles and water use fine pores, and larger particles in tiny amounts a “leak route”; whole cells cannot pass.

Permeability is therefore never zero and constantly changes in everyday life: after a meal, during exercise or stress it fluctuates without anything being wrong. The task also differs by section. The small intestine has to absorb a lot, the large intestine mainly water, and that is where the densest mass of bacteria lives.

The barrier has several layers. On the outside is mucus, whose main building block, mucin 2, is made by goblet cells. In a healthy large intestine, its inner layer is almost free of bacteria. Defence substances work within the mucus: IgA (secretory IgA) The antibody of the mucous membranes. It is released into the gut in large amounts, where it holds germs in the mucus without causing inflammation. More in the chapter “IgA: the antibody that keeps the gut clean, and what vitamin A, D and omega-3 have to do with it” binds bacteria before they reach the cells, and in the small intestine Paneth cells release germ-killing proteins such as defensins. The immune system waits beneath the cell layer. In the small intestine the Mucus layer A gel layer of mucins on the gut wall that keeps bacteria at a distance. In the colon, the inner layer is almost free of microbes. More in the chapter “The mucus layer and additives” is thinner and patchier so that nutrients can get through; there the germ-killing proteins take on a larger share of the protection.

The barrier renews itself constantly. New cells form from stem cells at the base of the gut crypts, migrate upward and are shed after about three to five days. This is one of the fastest turnover processes in the body, and it makes the lining vulnerable to anything that disturbs cell division, but also surprisingly good at repairing itself. Small damage usually heals within days.

The bacteria themselves help: the Butyrate A short-chain fatty acid and the main energy source for the cells of the colon wall. It strengthens the barrier and dampens inflammation. More in the chapter “Butyrate and other short-chain fatty acids” they produce from fibre is the main energy source of the cells of the large intestine and strengthens the connections between them. The nerves of the gut wall and the Mast cells Immune cells beneath the skin and mucous membranes, filled with histamine and other messengers. They raise the alarm in allergies, infections and stress. More in the chapter “Mast cells: alarm cells in the gut, histamine and the disputed MCAS”, the alarm cells of the lining, also help control tightness. That is why stress can noticeably change it.

Mucus with IgA, a tight cell layer and a calm immune system keep bacteria inside the gut.

Disrupted state: causes and effects

Alcohol, certain painkillers (NSAIDs such as ibuprofen), infections and heavy physical strain can temporarily make the barrier more permeable. Bacterial components then reach the tissue and irritate the immune system. With alcohol, its breakdown product and damage to the connections play a role, especially in larger amounts. NSAIDs block substances that protect the lining and also burden the cells' power plants. They therefore damage not only the stomach but often the small intestine too (NSAID enteropathy), which you hardly notice yourself. Endurance exercise in the heat, such as a marathon, also makes the gut briefly more permeable, because blood flow to the gut falls in favour of the muscles and skin.

Chronic stress, lack of sleep, a low-fibre diet and a one-sided flora also weaken the barrier over weeks. A one-sided flora supplies less butyrate, and a thinner mucus lets germs closer to the wall. In older people the barrier is often less tight; in premature babies it is not yet mature. In severe liver disease it is also demonstrably disturbed.

In Coeliac disease An autoimmune disease in which gluten damages the lining of the small intestine. It is diagnosed with a blood test and usually a biopsy while you are still eating gluten. More in the chapter “Lactose, fructose, gluten: making sense of intolerances” and Inflammatory bowel disease Umbrella term for Crohn’s disease and ulcerative colitis: long-term, relapsing inflammation of the gut that needs medical treatment. More in the chapter “Immune system and inflammation”, increased permeability is well documented. In coeliac disease, gluten triggers an immune reaction in the lining that damages the connections; on a gluten-free diet it usually recovers. Whether increased permeability is also a cause of Irritable bowel syndrome Recurring abdominal pain linked to bowel movements, without tests finding another cause. Today it is understood as a disorder of gut–brain interaction. More in the chapter “The gut-brain axis”, allergies or tiredness is disputed. In IBS it is found in some of those affected, especially after an infection, but whether it is cause or consequence of the symptoms is unresolved. Often the two go together: inflammation makes the gut permeable, and permeability keeps the inflammation going.

Be careful with tests: according to current knowledge, the commonly offered zonulin test in stool or blood does not reliably measure how permeable the gut is. Scientifically, permeability can be measured with sugar molecules that you drink and then find again in the urine. But that is a research method with no everyday value. The assumption that bacterial components in the blood (“ Endotoxin (LPS) A component of the outer coat of certain bacteria. When it reaches the blood, it triggers inflammatory responses. ”) cause many metabolic and mood problems is also a hypothesis. That the barrier plays a part is plausible; for an individual it cannot be proven.

If one layer fails, the others have to do more. In Crohn's disease of the Ileum The last section of the small intestine. It recovers bile acids, absorbs vitamin B12 and joins the colon via the ileocaecal valve. More in the chapter “Where the small intestine meets the colon: ileum, valve and caecum”, for example, the Paneth cells often do not work properly, and bacteria get closer to the lining. For everyday questions this means: the barrier is robust and usually heals by itself if you know the recurring triggers and reduce them.

Thin mucus and gaps between cells: bacterial fragments reach the tissue.

Where it comes from and where it leads

The same symptoms can have different roots. This map shows what may be involved in this problem and what may follow from it.

Connections, not certainty: a link means “can”, not “must”. What applies to you is best clarified in a talk with your doctor.

What often helps

Lifestyle

Diet, exercise, sleep, social contact and dealing with stress.

Fibre from whole foods Bacteria turn it into butyrate, which feeds the gut cells. In a mouse study, fibre even prevented germs from passing through a damaged barrier into the blood. Increase slowly if your gut is sensitive. Plausible How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open. [1]
Cut down on alcohol Alcohol increases the permeability of the gut lining, especially in larger amounts. A few days without alcohol are often enough for the lining to recover. Promising How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open.
Eat highly processed foods with emulsifiers less often In a small study, the emulsifier carboxymethylcellulose (E466) let bacteria penetrate the protective mucus layer in some individuals. More in the chapter on the mucus layer. Plausible How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open. [2]
Pace effort in the heat For long endurance sessions in the heat: drink enough, adapt your pace, do not push to the limit on an empty stomach. If you regularly get diarrhoea or cramps after runs, breaks and a slower build-up do your gut good. Promising How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open.

Natural supplements

Supplements do not replace a medical check-up. Discuss dosage and interactions with your doctor or pharmacist.

Glutamine In a randomised trial, glutamine (3 × 5 g daily) clearly improved symptoms and permeability in IBS after a gut infection. The trial was criticised for its methods and has not yet been independently confirmed. Promising How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open. [3][4]
Zinc Zinc plays a role in renewing the gut lining. A benefit is mainly to be expected if a deficiency has been confirmed. Plausible How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open.

Medical treatments

Information, not a treatment recommendation. Decide together with a doctor. Approval and availability differ from country to country.

Rule out coeliac disease Get a blood test for tissue transglutaminase antibodies while you are still eating gluten. Coeliac disease is the most common well-documented cause of a disturbed barrier. Established How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open. [5]
Review painkillers If you regularly take NSAIDs such as ibuprofen or diclofenac, talk to your doctor about alternatives. Iron deficiency or unexplained anaemia while taking NSAIDs can also point to small-bowel damage. Well supported How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open. [6]
Have inflammation measured in the stool With diarrhoea, mucus or blood in the stool, weight loss or night-time symptoms, faecal calprotectin helps distinguish inflammatory bowel disease from IBS. Well supported How we rate the evidence Established Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies. Well supported Several randomised studies in humans with largely consistent results. Promising Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies. Plausible Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms. Experimental Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open. [5]

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How we rate the evidence

Trust score 5 of 5:Established: Recommended in medical guidelines or supported by several consistent meta-analyses of randomised human studies.
Trust score 4 of 5:Well supported: Several randomised studies in humans with largely consistent results.
Trust score 3 of 5:Promising: Single randomised or controlled studies in humans, not yet independently confirmed — or many consistent observational studies.
Trust score 2 of 5:Plausible: Two cases: first observational or pilot studies with small samples — or a settled basis that is not in dispute, such as movement, sleep or meal pauses. But not tested in humans for symptoms.
Trust score 1 of 5:Experimental: Barely studied in humans. Mainly lab and animal studies or theoretical reasoning; whether it helps is open.

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