Bacteriophages: the hunters in the gut

Viruses that only infect bacteria are among the most numerous entities in the gut. What they do there.

How solid is the research? Plausible

That phages help steer the microbiome is well documented in the lab and in animal models. In humans, the research is still young: there are observational studies and a few small controlled trials.

Healthy state

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. , or phages for short, are viruses that infect only bacteria. They cannot infect human cells. They make up most of the “virome”, the whole of all viruses in the gut. Per gram of stool there are probably billions of virus particles, about as many as bacteria, perhaps more. The often-quoted figure of “ten times more phages than bacteria” is considered outdated, and numbers vary with the measuring method. There are also viruses that infect fungi, amoebae and human cells, but they are in the minority.

Most of these phages are still unknown: for most genetic finds, it is impossible to say which bacterium they infect. Experts speak of “dark matter”. What is known, for example, is that so-called crAss-like phages, which infect Bacteroides species, are very common in many people. In humans, the virome forms in the first years of life together with the bacteria. Diet, age and place of residence shape it later.

It is striking how personal and stable it is. In a study that followed healthy adults for months and up to more than two years, each person had their own “core” of phages that stayed remarkably constant over time. Hardly any phage was found in most participants. As with the bacterial fingerprint, there is not one healthy phage picture but many.

Each phage specialises in certain bacteria. If one species becomes more common, its phages find more prey and can limit it so that no species becomes too powerful. This principle is known as “predator and prey”: the numbers on both sides fluctuate without the prey dying out, because bacteria constantly change their surface to escape phages and have their own defence systems (the best known is CRISPR). This arms race keeps diversity high. How strongly it works in the human gut is still unclear, because most evidence comes from the lab and animal models.

Many phages also live quietly in the genome of their bacteria and multiply only together with them (“dormant” or temperate phages). In a healthy gut the relationship is more of a coexistence. Lab findings also suggest that phages can attach to gut mucus and so keep watch at the boundary with the gut wall, where bacteria could be especially dangerous. Small amounts of phages are also taken up and found inside the body. Whether this matters for the immune system is open.

Phages hunt the most common species, others rest quietly in their bacteria's genome.

Disrupted state: causes and effects

Stress for the bacteria, for example from antibiotics, inflammation or oxidative stress (aggressive oxygen compounds), can wake up dormant phages. The principle: damage to the genome triggers an emergency response in the bacterium, and the dormant phages in its genome use it as a signal to multiply and burst the cell. In this way they can destroy many hosts at once and shift the microbiota without any new germ arriving from outside.

In 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” the phage community is clearly altered. In one study, a particular group of phages (Caudovirales) was increased in Crohn’s disease and ulcerative colitis even though bacterial diversity fell at the same time, so the change could not be explained by more prey alone. The community is also altered in colorectal cancer and liver cirrhosis. Whether this is cause or consequence is unclear. Both are conceivable: inflammation wakes phages, and phages could fuel inflammation by bursting bacteria. So far this is a hypothesis.

Phages can also transfer genes between bacteria. Well-known examples are toxins: the genes for the Shiga toxin of certain E. coli strains and for cholera toxin are carried by phages. Resistance genes can be passed on in this way too, but this probably happens less often in the gut than in the environment. For healthy people this is no cause for worry in everyday life.

Antibiotics change not only the bacteria but also the viruses that depend on them. After a course, the phage pattern shifts, and it can take months until it settles again. A faecal transplant transfers viruses along with bacteria. In recurrent 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” infections, this is a possible part of its effect. This counts as a hint rather than proven.

Putting this in perspective matters: viruses are hard to measure, methods differ from study to study, and a large part of the sequences cannot be assigned to any phage. Statements such as “phages X are good” or “phages Y make you ill” are currently not possible for individuals. Accordingly, commercial tests of the virome are not meaningful.

Stress wakes resting phages: they multiply and bacteria burst.

What often helps

Lifestyle

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

Stabilise the microbiome as a whole Phages follow their host bacteria. Diet, age and where you live shape the phage community. A diverse microbiome also carries a diverse phage ecosystem. The best levers are therefore the same as for the bacteria: a varied, plant-rich diet with fibre. 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. [1][2]
Fermented foods Fermented foods contain not only bacteria but also their phages. Whether this matters for the gut has not yet been studied. 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.
Antibiotics only when needed Antibiotics put bacteria under stress and can wake dormant phages. When they are needed, take them as prescribed. They do not help against viral infections such as colds or flu. 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]

Natural supplements

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

Phage supplements A product with phages against E. coli reduced the amount of E. coli in the stool of healthy people in a small crossover study and was well tolerated. In a second study, combined with a probiotic, there were signs of better well-being and more beneficial bacteria. A clear benefit for symptoms has not been shown. 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][4]
Not for bloating or irritable bowel Phage products have not been studied for irritable bowel or bloating. They should not be used to “optimise the virome”, because there is no target value. 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.

Medical treatments

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

Phage therapy For infections with resistant germs, specialist centres use targeted phages. In many countries this is so far only possible as an individual treatment. Find out which options exist in your country. 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. [5]
Phages in faecal transplants A faecal transplant also transfers phages. First small studies suggest that they could contribute to its success. 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. [6]
No virome tests without a question There is no recognised procedure for deriving a diagnosis or treatment from the viruses in stool. If you have symptoms, have the usual examinations done first. 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.

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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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