Immune system and inflammation

The gut trains your defences and can also upset them unnecessarily.

How solid is the research? Promising

That the microbiome shapes the immune system is well established. That “silent inflammation” from the gut causes symptoms such as tiredness or skin problems is a hypothesis with first indications.

Cause or consequence? Cause and consequence

The gut’s immune system depends on a varied flora. If it is weakened, opportunistic germs find it easier to gain ground.

Healthy state

The gut is the largest contact surface between the body and the outside world. Over an area of around 30 square metres it meets food, trillions of bacteria and the occasional pathogen every day. That is why most of the immune system sits there: a large share of the immune cells lies in and around the gut, organised in lymphoid tissue such as the Peyer's patches of the small intestine, which you can picture as a guard post with a built-in school.

This is how it works: specialised cells in the gut wall, the M cells, take small samples from the gut contents and pass them to scavenger cells, the dendritic cells. These examine what they received and show it to the T cells. Depending on the signal, the T cells decide whether to start a defence or to stand down. The normal outcome is calm: the immune system learns to tolerate food and beneficial bacteria. This is called Oral tolerance The ability of the immune system to tolerate food protein taken up via the gut as harmless, mediated mainly by regulatory T cells. More in the chapter “Allergies and intolerances: how the gut learns to tolerate food”. Without it, every meal would set off a defence reaction.

Beneficial bacteria take part in this education. Their Short-chain fatty acids Acids such as acetate, propionate and butyrate that gut bacteria make from fibre. They nourish the gut wall and act throughout the body. More in the chapter “Butyrate and other short-chain fatty acids”, above all 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”, promote regulatory T cells, which slow the immune system down. Vitamin A plays a part too: immune cells in the gut make retinoic acid from it, which drives these braking cells and 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” production. The antibody secretory IgA holds bacteria in the mucus without causing inflammation (more in the chapter on IgA).

The balance goes further. Some bacteria stimulate a group of T cells (Th17) that keep the lining and its defences slightly on alert. In the right dose that is useful; too much promotes inflammation. Viruses are part of it as well. Countless Bacteriophages Viruses that only infect bacteria. In the gut there are probably about as many phages as bacteria, perhaps more, and they help determine which bacteria prevail. More in the chapter “Bacteriophages: the hunters in the gut”, which infect bacteria, live in the gut, and occasionally viruses that infect us. Fungi such as Candida live harmlessly in the gut of many people; the immune system keeps them in check. With parasites such as worms it was different in evolution: they trigger their own type of immune response and often dampen the rest of the defences at the same time. This is one reason the hygiene hypothesis is discussed (see below).

The gut immune system develops most strongly in the first years of life. Birth, breast milk, the first solid foods and contact with many microbes shape it. In old age the fine-tuning declines and the flora often becomes more one-sided. Both the young and the old immune system react more sensitively to disturbances than that of a healthy adult.

Bacteria make butyrate, which strengthens regulatory T cells. The immune system stays calm.

Disrupted state: causes and effects

If the calming signals are missing, for example because the flora is not very diverse, fibre is lacking or antibiotics have thinned out species, the immune system in the gut is irritated faster and more strongly. A persistent, low-grade inflammation can develop. This is a mild constant activation that shows up only in markers such as CRP in the blood or Calprotectin A protein from white blood cells measured in stool. Raised levels point to inflammation in the gut. More in the chapter “Gut tests: what they show and what they do not” in the stool, not necessarily as pain. It is important to distinguish it from the bowel diseases Crohn's disease and ulcerative colitis, where the inflammation is clear, visible and needs treatment.

The hygiene hypothesis plays a role, today more often called the “old friends hypothesis”. It says that too little early contact with diverse microbes trains the immune system poorly. Frequently named factors are caesarean birth, little breastfeeding, many antibiotics early in life, little contact with nature and having few or no siblings. The link with allergies and Autoimmune disease A disease in which the immune system attacks the body's own tissue, for example the thyroid in Hashimoto's or the pigment cells in vitiligo. More in the chapter “Autoimmune diseases and the gut: Hashimoto's, vitiligo, type 1 diabetes and more” is visible in population data. But it is statistical, not instructions for the individual. And it does not mean you should deliberately expose yourself to germs that make you ill.

Stress also acts on the gut immune system. Via nerves and stress hormones it changes the permeability of the lining, the composition of the flora and the activity of 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”. Lack of sleep raises inflammatory markers in the blood. Some people react much more strongly, for example after a gastrointestinal infection, after which the immune system in the gut sometimes “smoulders” for a while.

Honesty matters when it comes to consequences. Tiredness, joint pain or skin problems are linked to inflammation from the gut, but for most of these links it is unclear what is cause and what is effect. A finding such as “raised inflammation values” also says little without context: infections, excess weight, smoking and gum inflammation raise the same markers. A stool test of gut immune cells does not replace a diagnosis.

Another misconception: “boosting the immune system” is not the goal. Too much defence is just as much of a problem as too little, as in allergies and autoimmune diseases. What is meant is a well-calibrated, tolerant immune system, and it is supported by variety in diet, microbes and everyday life.

Less butyrate, less braking: immune cells react faster and inflammation can develop.

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.

Mediterranean diet In a one-year study with 612 older people, a Mediterranean diet changed the gut microbiota. The bacteria it promoted were linked to lower inflammatory markers. 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. [1]
Fermented foods In a randomised trial, they lowered 19 of the 93 inflammatory markers measured. 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. [2]
Sleep and recovery Lack of sleep raises inflammatory markers in the blood. Enough sleep has a calming effect on the immune system. Regular sleep times also help the gut's internal clock. 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.
Plant variety instead of single miracles Many different plants per week feed many groups of bacteria that give the immune system calming signals. This means vegetables, fruit, legumes, nuts, whole grains, herbs. Increase slowly if your gut is sensitive. 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. [1]
Exercise Regular moderate exercise is linked to lower inflammatory markers and a more diverse gut flora. Extreme strain without breaks can have the opposite effect. 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. [3]

Natural supplements

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

Vitamin D In meta-analyses, vitamin D somewhat improved IBS symptoms, but the studies were small and very different. Useful mainly 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. [4]
Omega-3 fatty acids They help regulate inflammation. For gut symptoms the effects are inconsistent. 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 inflammatory diseases Faecal calprotectin and CRP in the blood help distinguish inflammatory bowel disease from IBS. 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]
Have unusually frequent infections or autoimmune signs checked If you are ill unusually often, have long-lasting infections or several autoimmune symptoms at once, you can have this checked by a doctor, for example with a blood count and immunoglobulins. Behind it there may be a treatable immune deficiency or coeliac disease. 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.

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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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