Battle for iron – why iron availability shifts the balance of power in the microbiome

Day after day, a battle rages in our bodies over a trace element. Pathogens fight with helpful bacteria for a rare metal. The body tries to intervene. But often it can only watch as competing groups fight it out to see who gets the rare raw material and can thus dominate the intestines.

Countless commercials promise quick help for iron deficiency. Swallow a tablet every day and your iron supply will be just right. This completely ignores the fact that only very few people have a real iron deficiency and careless supplementation can lead to far-reaching problems. Understanding the interplay between iron and the microbiome is essential in order to avoid causing damage and still have an optimal iron supply.

Iron is life

People need iron. There is no question about it. Many biological processes cannot function without this fundamental element. Most of it is found in the haemoglobin of red blood cells. Iron binds oxygen in the lungs and transports it to tissues and organs. Without iron, there would be no efficient oxygen transport, no matter how strong your lungs and heart are.
Iron is also found in a large number of enzymes. It is essential in our mitochondria, where it activates the formation of ATP, the universal energy currency in our body.
It is also needed in the bone marrow to form new erythrocytes, as well as for building proteins, synthesizing our DNA and many other metabolic processes.
Last but not least, our immune system and our brain rely on a sufficient supply of the metal in ionic form.

In short: no life without iron.

Gold for the bacteria

What applies to humans also applies to bacteria. Iron is also an essential building block of life for these tiny creatures. It is therefore important for the microorganisms in our body to have access to it. However, the bacteria in our intestines do not swim around on their own, but are surrounded by trillions of other microorganisms. They therefore have to assert themselves in order to be able to mine the rare “gold”. They have developed fascinating techniques to do this.

The path of iron into the intestine

But how does the iron get to the microorganisms in the first place? Isn’t it already completely absorbed in the small intestine after ingestion? The answer is clear: no. Depending on the form of iron and requirements, only parts are absorbed, often in the range of 10-20%, and the rest ends up in the large intestine, where the battle for the valuable iron begins.

The tactics of pathogens

Pathogenic bacteria have developed extremely effective systems to get hold of the coveted metal. They attract it like a magnet with their special iron absorption systems, the so-called siderophores. They therefore benefit particularly from an excess of iron, which leads to a strong increase in pathogens and causes inflammatory processes or directly triggers diseases.

The “good guys” strike back

However, very valuable bacteria, such as lactobacilli or bifidobacteria, have also developed strategies. Although they do not have such efficient iron uptake systems as the pathogenic bacteria, they have learned to get by with extremely little iron . They use a trick to do this: instead of iron, they sometimes use manganese, which other bacteria cannot use, making them less dependent on iron.

The body intervenes

And our body does not stand idly by either:

If the body registers a sufficient or excess iron supply, the hormone hepcidin is released, which ensures that less iron is absorbed into the blood. Conversely, it can also ensure that more iron is absorbed.

It therefore takes care of itself first and foremost and manages its own supply very meticulously. However, the body also intervenes in the battle for iron. By releasing iron-binding proteins such as lactoferrin, it removes the trivalent iron ion coveted by bacteria from the intestine. This protects the body well against infections, but in the worst case, if overdone, can lead to iron anemia, i.e. a lack of iron. The system overreacts.

But the pathogens can strike back: either they use the aforementioned siderophores, the iron uptake systems, or they dock onto the body’s iron-binding proteins. In principle, they are like pirates who attack the body’s fully loaded iron ships and snatch the coveted metal.

Iron and the microbiome – a delicate balance

This battle for iron therefore takes place between the pathogenic bacteria, the beneficial intestinal inhabitants and our body, creating a balance which is, however, very susceptible to disruption. The worst interference in this finely balanced system usually comes from us, in the form of iron supplements.

The devastating study with African babies

To shed more light on this, it is worth taking a look at a study with babies from Kenya. Here, infants who generally suffered from iron deficiency in Africa were given special iron-enriched food to compensate for the existing iron deficiency.
However, instead of an improvement in health, exactly the opposite was achieved. Suddenly, diarrheal diseases increased, pathogenic Escherichia coli species increased dramatically and the beneficial bifidobacteria decreased.
Even when the dose was radically reduced to only one fifth due to the diseases, the children showed no improvement. What had happened? We now know that the microbiome is particularly sensitive in the first few months of life. It first has to be formed. Extremely high levels of bifidobacteria from breast milk create excellent conditions for further development.

However, diversity and therefore resilience are very low at this stage. The addition of iron encouraged the few pathogens present and allowed them to assert themselves in the still fragile microbiome. The result was dysbiosis, i.e. a pathological change in the microbiome. Instead of helping the children, they were massively harmed.

Caution for pregnant women, elderly people and patients

However, pregnant women, older people and patients with chronic inflammatory bowel diseases such as Crohn’s disease or ulcerative colitis are also particularly susceptible to negative influences from iron. It is particularly challenging for the latter, who usually suffer from iron deficiency anemia and therefore require iron supplementation.

Oral iron therapy can lead to an imbalance of the microbiome in people with chronic inflammatory bowel disease (IBD). The diversity of beneficial intestinal inhabitants decreases, e.g. those that form the particularly sought-after short-chain fatty acids, and pro-inflammatory bacteria increase, which puts further strain on the already inflamed intestine. This is why IBD patients are often treated with intravenous iron, which has no effect on the intestinal flora.

Most women during pregnancy have an increased iron requirement and iron supplements are standard in medical care. However, little research has been carried out into the effects of oral iron supplementation on the maternal and fetal intestinal flora. It can be assumed that, similar to non-pregnant women, a promotion of iron-loving bacteria could occur. However, clear studies on this are still lacking.

The last risk group, older people, already largely have an altered intestinal flora, the diversity of which decreases over time, and reduced iron absorption. Excess iron in the intestine increases this effect.

What are the biological effects of iron deficiency and excess?

Both iron deficiency and excess iron in the intestine have a variety of negative biological effects.

Excess iron

On the one hand, excess iron in the large intestine can lead to the dysbiosis discussed, as the balance of bacteria is shifted unfavorably. Due to the reduction in helpful intestinal bacteria that produce short-chain fatty acids, the intestinal wall is no longer sufficiently supplied and can become inflamed. At the same time, this is exacerbated by the increase in pathogens.
In the worst case, leaky gut syndrome can occur, in which the intestinal wall becomes permeable and food components, as well as parts of the bacteria such as lipopolysaccharides or whole bacteria, enter the systemic circulation .

As well as reducing helpful bacteria, iron promotes pathogenic germs and can lead to infections. In addition, excess iron promotes inflammation, which leads to the release of hepcidin, which specifically removes iron from the body and can in turn lead to iron anemia.

Free iron in the intestine also generates oxidative stress and can also selectively influence the microbiota. Unbound bivalent iron promotes the formation of reactive oxygen species (ROS) in the intestinal contents. These oxidize the environment of the large intestine and damage the microorganisms and the host tissue. This promotes oxygen-tolerant bacteria rather than strictly anaerobic microorganisms, which usually make up the majority of beneficial gut bacteria and react strongly to ROS.

In addition, oxidative stress directly damages the intestinal mucosa, as it is attacked by the reactive oxygen species.

Iron deficiency

An iron deficiency in the large intestine in turn leads to a deterioration in the immune response and to mucosal atrophy, in which the mucosa is degenerated and inflammation and infections are also promoted, as well as potentially increasing the risk of cancer. Here too, the bacteria responsible for the production of short-chain fatty acids are reduced.

As a reminder, all of this happens when too little iron arrives in the large intestine after absorption in the small intestine, or too much. We are not talking here about too little or too much absorption in the small intestine and the associated systemic effects, but exclusively about the conditions in the large intestine.

The shape of the iron is a decisive factor

But as if the existing balance wasn’t complex enough, the form of the iron also determines whether there is a lack or excess of iron.

Heme iron from animal foods

Heme iron, a special form that is bound to the red blood pigment and therefore occurs exclusively in animal foods, plays a special role here.
Heme, in the middle of which is the bivalent iron ion, is known in humans for transporting oxygen in the blood. However, myoglobin in the muscle and the cytochromes in cellular respiration, i.e. energy production, are also dependent on haem iron. This is why heme iron is highly sought after in the body.

If this heme iron reaches the small intestine via animal foods such as red meat, liver and other offal or poultry and fish, it is very efficiently absorbed there.
Up to 35% is used directly by the body, as it particularly favors heme iron due to its special importance.

A diet rich in meat leaves less iron for the large intestine. However, this iron is particularly biologically active as it is easily utilized. This makes it easier to have an iron surplus.

Iron from plant-based foods

Plant-based foods have no heme iron and only approx. 2-10% of the iron is absorbed in the small intestine: Although more iron is available in the large intestine, the trivalent iron ions predominate in the large intestine in plant-based foods. These must first be mobilized by an easily disruptible reduction before the bacteria can use them. In addition, they are often complexed and kept in the biologically less active trivalent form.

Although plant-based foods allow larger amounts of iron to enter the large intestine, the microbial effect is limited. This means that an excess of iron does not occur so quickly.

Iron from meat or plants?

Although little iron arrives in the intestine with a pure meat diet, it is optimally available and highly reactive, so that it promotes iron-loving germs. Even small amounts have a major biological effect. This is because haem iron in particular reduces diversity in the intestinal microbiome, increases inflammatory processes and promotes oxidative stress and iron-dependent, often pathogenic germs.
Inorganic iron from a plant-based diet is less selective, does not promote aggressive iron competition and weakens negative effects. Iron from a plant-based diet is therefore more microbiologically compatible.

The most important statements on iron and the microbiome

1. the largest amount of iron ends up in the large intestine

The majority of the absorbed iron is not absorbed in the small intestine, but ends up in the large intestine.

2. iron is an essential limiting nutrient in the large intestine.

The microbiome is influenced by the competition of bacteria for iron and the removal of these metal ions by the body.

3. supplementation influences the microbiome

If iron is supplemented orally, the microbiome is typically shifted towards fewer “good” and more potentially “bad” bacteria, with the corresponding negative effects.

4. complex effect

The effect of iron on the body is complex and depends on the amount, availability and source.

5. iron promotes oxidative stress

Iron, which is freely present in the intestine, promotes oxidative stress and influences intestinal integrity and the immune system.

6. both are harmful

Both iron deficiency and excess iron are harmful to the microbiome and consequently to the body.

7. caution with iron supplementation

Iron supplementation must be approached with great caution so as not to trigger other serious negative effects in the hope of curing iron anemia.

But what can you do now? To supplement or not? There is often a great deal of uncertainty in view of this complex quantitative situation. However, some robust principles can be derived from the current literature.

10 evidence-based tips for optimal iron supply and gut health

1. iron requirements should primarily be covered by a
varied diet.

A diet rich in iron is better than supplementation. Lean, but ideally less red meat, fish, wholegrain cereals, pulses, nuts and green vegetables are good candidates here.

2. only use iron supplements if there is a proven
deficiency.

Do not rush to take the pill, as this can lead to damage to the microbiome.

3. take low doses of supplements and take breaks

The latest studies show that the body’s own hepcidin hormone is released when iron is first administered and can block further iron absorption for up to 24 hours. Therefore, the practice of swallowing several portions of iron a day is generally of little benefit, but causes very high hepcidin levels. It is therefore better to take a single daily dose and, if necessary, an interval intake on the second day. This alternate-dose principle has been shown to lead to higher iron absorption and also improves tolerability.

4. note the optimum time for supplements

The body’s own hepcidin level is particularly low in the morning. For this reason, iron supplements should preferably be taken in the morning on an empty stomach, when absorption is most efficient. If this is not possible due to a sensitive stomach, it should be taken with a light meal, but without tea or coffee.

5. plant sources of iron are better than animal sources of iron

Non-heme iron is absorbed less efficiently and does not lead to an excess so quickly. Lentils, beans, oatmeal, pumpkin seeds or green leafy vegetables are good sources. The simultaneous administration of vitamin C increases the rather poor absorption of iron from plant sources in the small intestine, so that less unbound iron ends up in the large intestine.

6. avoid too much red meat

Red meat contains very high amounts of biologically active heme iron, which can lead to unfavorable changes in the intestinal flora.

7. avoid iron inhibitors at mealtimes

If iron inhibitors such as black or green tea, coffee or red wine are drunk with an iron-rich meal, they affect absorption in the small intestine and too much iron ends up in the large intestine, where it can have an unfavorable effect on the intestinal flora. An interval of one to two hours is recommended. This is particularly relevant with supplements or very iron-rich meals, because otherwise far too much unbound iron remains in the intestinal lumen.

8. fiber and prebiotics feed the intestinal flora

A diet rich in fiber (whole grain products, vegetables, nuts, fruit) and prebiotics such as inulin serve as food for helpful intestinal bacteria. Studies also show that certain prebiotics can improve iron absorption. In addition, fiber prevents constipation as a side effect of iron supplements.

9. incorporate fermented foods and probiotics

Fermented foods such as sauerkraut, yoghurt, kimchi, kefir or kombucha enrich the intestinal flora and keep negative bacteria in check. In addition, certain probiotic strains of Lactobacillus fermentum or Lactobacillus plantarum 299v have been shown to increase the body’s absorption of iron. A daily shot of helpful bacteria therefore has a dual function: it strengthens the intestinal flora and indirectly improves the iron supply.

10. if you take iron supplements, take well-tolerated ones:

Conventional bivalent iron tends to leave a lot of free iron in the large intestine. There are new experimental approaches that aim to make iron more readily available. In infants, for example, it was found that iron in nanoparticulate form caused significantly fewer pathogenic germs to proliferate and less intestinal inflammation occurred.

Conclusion: taking the power struggle seriously

It is worth thinking about how the iron supply can be optimized so as not to unbalance the intestinal microbiome. Neither too much nor too little available iron in the intestine is desirable.
Unless an iron deficiency has been identified, iron supplements should not be used prematurely.

The battle for iron is a massive power struggle in the body, which can quickly escalate into a defeat for the microbiome and thus for the body if iron is administered too lightly.

List of sources:

Jaeggi 2015, Gut – Iron fortification adversely affects the gut microbiome in infants (Kenya study), DOI: 10.1136/gutjnl-2014-307720

Kortman 2014, FEMS Microbiol Rev – Nutritional iron turned inside out: intestinal stress from a gut microbial perspective, DOI: 10.1111/1574-6976.12086

Lee 2017, Gut – Oral versus intravenous iron therapy in IBD distinctly alters gut microbiota and metabolome, DOI: 10.1136/gutjnl-2015-309940

Monteagudo-Mera 2023, Front Microbiol – Impact of inorganic iron and haem on the human gut microbiota (in vitro batch culture study), DOI: 10.3389/fmicb.2023.1074637

Yilmaz 2018, Pharmaceuticals (Basel) – Gut Microbiota and Iron: The Crucial Actors in Health and Disease, DOI: 10.3390/ph11040098