Opportunistic pathogens

Germs that are always there and only become a problem when the balance tips.

How solid is the research? Promising

That Enterobacteriaceae increase strongly during gut inflammation is well observed in humans. Whether they are a cause or a consequence has mainly been studied in animal models.

Cause or consequence? Rather a consequence

Opportunists grow when space frees up — after antibiotics or without stomach acid. They are a consequence, but cause symptoms themselves.

Healthy state

A healthy gut also hosts germs that can cause disease, such as certain Escherichia coli, Klebsiella, enterococci or Clostridioides difficile A bacterium that can spread after antibiotics and cause severe diarrhoea with its toxins. More in the chapter “After antibiotics: C. difficile and faecal transplants”. Experts call them pathobionts or opportunistic pathogens: they seize the opportunity when the balance tips. The difference between colonisation and infection is important. A germ can sit in the gut for months or years without causing harm. It becomes a problem only when it multiplies strongly, produces toxins or reaches a place where it does not belong, such as the urinary tract or the blood.

The body keeps them small on several levels, from top to bottom. Saliva contains defence substances. Stomach acid (pH 1 to 3) kills a large share of swallowed germs. Bile and the digestive juices of the pancreas inhibit bacterial growth in the small intestine. The “cleaning wave” between meals (technical term: Migrating motor complex A wave of muscle contractions that sweeps the stomach and small intestine empty about every one and a half to two hours when fasting. Eating interrupts it. More in the chapter “Intermittent fasting and meal timing: 16:8, 5:2 and Ramadan”) pushes leftovers and germs towards the large intestine. And the closing muscle between small and large intestine, the ileocecal valve, holds back the dense colonic flora.

At the gut wall comes the next layer of protection. The wall is covered with mucus, whose inner layer is almost germ-free in healthy people. Specialised cells in the crypts (Paneth cells) release defence substances that punch holes in bacteria. 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”, an antibody in gut mucus, binds germs and keeps them away from the wall. The cells themselves are tightly sealed by Tight junctions Protein connections that hold the cells of the gut wall tightly together. They determine what can pass between the cells. More in the chapter “The gut barrier”. As long as the pathobionts stay at the edge, the immune system mostly tolerates them.

On top of this comes competition in the large intestine itself. Pathobionts stay small because beneficial bacteria compete with them for food and space. In addition, the large intestine is almost free of oxygen, which favours the specialists among gut bacteria.

This competition is called colonisation resistance. It includes the fight for food and space, inhibitory substances that bacteria produce against each other (bacteriocins), 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” that keep the environment slightly acidic, and converted Bile acids Substances made by the liver that make fat digestible. About 95 percent are reabsorbed in the last part of the small intestine; gut bacteria transform the rest. More in the chapter “Bile acids: when bile causes diarrhoea”. A dense, diverse Microbiome, gut microbiota The community of all microbes in the gut, mainly bacteria, plus viruses, fungi and archaea. Most live in the colon. More in the chapter “Building microbial diversity” thus leaves no niche for intruders.

Helpful bacteria keep the gut low in oxygen. Pathobionts stay few.

Disrupted state: causes and effects

Antibiotics, infections and inflammation weaken the beneficial 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” producers. Less butyrate means the gut cells leave more oxygen unused and more nitrate is formed. That antibiotics pave the way for germs like this was shown in mouse experiments: when the butyrate producers were missing, oxygen at the gut wall rose and Salmonella multiplied; with a supplied butyrate precursor the oxygen deficit returned and held them back.

This is exactly what Enterobacteriaceae such as E. coli and Klebsiella benefit from: they can use oxygen and nitrate and multiply strongly. This is regularly seen during flares of 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”. A vicious circle develops: inflammation promotes the pathobionts, and they in turn increase the inflammation. Whether a rise in Enterobacteriaceae is cause or consequence of inflammation is hard to separate in humans.

There are further triggers. Antibiotics are the most important: they also thin out the competitors. Acid blockers let more swallowed germs reach the gut alive, including from the mouth, and lower diversity. If the cleaning wave is too weak or bile is lacking, germs can overgrow in the small intestine (see the chapter on Small intestinal bacterial overgrowth (SIBO) Too many bacteria in the small intestine, where normally few live. Bloating and diarrhoea are typical; it is usually diagnosed with a breath test. More in the chapter “When the small intestine is too densely colonised”). Low-fibre diets also play a role: when bacteria lack food, some turn to the gut mucus. With age, diversity declines and the immune system works less precisely. Hospital stays, surgery, chemotherapy and immune weakness tip the scales further.

How do pathobionts make people ill? They produce toxins, trigger inflammation, damage 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”, ferment food into gas or migrate through the wall. In Crohn’s disease, certain adherent E. coli strains are more common. The gut is also the reservoir for many infections outside the gut: most urinary tract infections are caused by E. coli from the person’s own gut. Multi-resistant hospital germs can stay in the gut for months without being noticed. They are dangerous mainly during surgery or with immune weakness.

For perspective: a note of “elevated Klebsiella” or “too little E. coli” in a stool test says little on its own. Values fluctuate strongly, reference ranges are inconsistent, and many people are healthily colonised. What matters are symptoms, course and the question of what favoured the germ. Usually the pathobiont is the result of a disturbed environment rather than the actual root. It can still make symptoms worse.

Less butyrate: oxygen and nitrate enter the gut, Enterobacteria multiply.

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.

Possible causes
This problem
Possible consequences

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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 for the butyrate producers It strengthens the bacteria that keep the gut low in oxygen. In a mouse study, a high-fibre diet prevented Klebsiella from spreading. 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][2]
Build diversity A diverse microbiome leaves fewer niches open. More on this in the chapter on microbial diversity. 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]
Kitchen hygiene Handle raw poultry and eggs carefully, cook meat through, keep cutting boards separate and cool leftovers quickly to avoid infections with Salmonella or Campylobacter, which can disturb the balance. When travelling: safe water, cooked food rather than raw produce from an unsafe source. 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.
Breaks between meals The small intestine’s cleaning wave runs only when nothing is eaten for a while. Anyone who constantly eats small amounts leaves it little time. Three to four meals with breaks are a gentle start for many people. 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.

Natural supplements

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

Saccharomyces boulardii during antibiotics In meta-analyses, this probiotic yeast roughly halves the risk of diarrhoea during antibiotic treatment. Protection against C. difficile in adults is not established. Not with a central venous catheter, serious illness or severe immune weakness: in those cases the yeast can rarely enter the blood. 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. [4][5][6]
Herbal antimicrobials Oregano oil, berberine and similar products are often used against “dysbiosis”. There are hardly any human studies on specific pathobionts. They do not act selectively and also hit the beneficial bacteria. Experimental 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.
Iron only with a proven deficiency Many gut germs need iron to grow, and part of the iron taken stays unused in the gut. There are indications that high iron doses can favour unfavourable bacteria. So take iron not on suspicion but based on blood tests and after talking to a doctor. 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.

Acid blockers only as long as necessary Proton pump inhibitors reduce the diversity of the gut microbiota. Whether they increase the risk of C. difficile is disputed: observational studies say yes, randomised trials so far do not. 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. [7][8]
Stool test if an infection is suspected With persistent diarrhoea, have your stool tested for specific pathogens. Commercial “dysbiosis tests” without a medical question have little value. 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.
Antibiotics targeted and short If an antibiotic is needed: as narrow as possible and as short as necessary. They do not help against viral infections. Ask whether a narrower-spectrum drug is possible. 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.
Tell staff about hospital-germ colonisation If you know you carry multi-resistant germs in your gut, say so before surgery and hospital stays. Then precautions and suitable antibiotics can be chosen. In everyday life, colonisation usually has no consequences for healthy people. 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.

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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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