Meet hepcidin, the most important player in iron metabolism, that you’ve probably never heard of.
I’ve been focussing lately on nutritional dark matter – that is, the concept that we cannot understand or predict the health effects of individual foods, or of particular diet-styles, based on either their macronutrient composition (that is, their relative proportions of fat, protein and carbohydrate) or their micronutrient composition (that is, their vitamin and mineral content).
As I wrote in Nutritional Dark Matter: Understanding what really matters in your diet,
“Nutritional dark matter comprises a plethora of as-yet-undiscovered, or discovered but as-yet-uninvestigated molecules that exert as-yet-unknown or barely-known effects on human health. It’s highly likely that many of the apparently contradictory results of nutrition research studies are attributable to the interaction between nutritional dark matter and the infinite genetic, epigenetic and environmental variations that make each human being unique.”
In other words, the foods we eat are complex systems, and we eat most of these foods in mixed meals which constitute complex systems, and we ourselves are complex systems, so the interaction between these three complex systems is… well… complex!
And just in case that triple dose of complexity isn’t enough for you, nested within the complex system of a human being is yet another complex system: the gut microbiome. The gut microbiota play a key role in absorption of nutrients. And their human hosts respond to changes in microbiota composition by altering the availability of nutrients.
Iron is a case in point.
Iron: the double-edged sword
Iron is an essential mineral for most species on Earth, from the simplest microorganisms on up to the most complex multicellular life forms. In humans, iron is a key component of haemoglobin – the protein in red blood cells that carries oxygen around the body and delivers it to tissues – and myoglobin, which stores and releases oxygen within skeletal and heart muscle cells. Iron is also used in enzymatic reactions that synthesise amino acids, DNA, hormones and neurotransmitters, and it plays a vital role in immune function and in cellular respiration, the process by which the body extracts usable energy from food. Simply put, if we don’t have enough iron, we die.
And yet, excess iron is dangerous too. Iron is a potent oxidising agent which generates reactive oxygen species, a category of unstable, oxygen-containing chemicals that includes free radicals. Reactive oxygen species ‘steal’ electrons from molecules in our cells, initiating harmful chain reactions that can ultimately lead to cell death. Excessive iron accumulation1 causes damage to the liver, heart, pancreas, and endocrine glands. And we have no active mechanism for expelling excess iron from our bodies. (Blood loss, including menstrual blood loss, is a passive mechanism of iron loss, and explains the lower iron levels found in premenopausal women compared to men and postmenopausal women.)
Our bodies use two strategies to mitigate the harmful effects of iron. Firstly, very little of it is allowed to circulate in free form. After absorption in the upper part of the small intestine, most iron is encased in proteins: haem proteins, which include haemoglobin, myoglobin, cytochromes, and peroxidases; transport proteins, including transferrin and ferroportin; and storage proteins, including ferritin and haemosiderin. And secondly, the amount of dietary iron that we absorb is very tightly controlled. The average adult male eats 16 to 18 mg of iron per day, recycles around 25 mg of iron per day from his worn-out red blood cells and an additional few mg from his sloughed-off intestinal cells, loses only trace amounts – around 0.5 mg per day – via shed skin cells and in urine and faeces, and yet has only 3 to 4 grams of iron in his entire body. Requirements for iron are higher in children (due to rapid growth) and women of reproductive age (due to menstrual losses of approximately 2 mg per day of bleeding, and increased demand during pregnancy), but even they don’t absorb the vast majority of the iron that they consume. On average, men absorb only 6 per cent of the iron they take in, while premenopausal women average 13 per cent absorption. That’s just 1-2 mg per day, in normal circumstances.
Haem iron2 – that is, iron from the blood of animals – is absorbed at a high and fairly constant rate of 15 to 35 per cent, regardless of one’s iron status or current need for iron. Because we have so little control over haem iron absorption, our bodies exercise a great deal of discretion over the absorption rate of non-haem iron. Non-haem iron is found in plants, eggs and dairy products. Meat and poultry also contain non-haem iron3, derived from plants that the animal ate. The rate of absorption of non-haem iron varies more than ten-fold, from 2 to 20 per cent. While this absorption rate is certainly affected by other components of the meal, including vitamin C which boosts absorption, and phytates, tannins, polyphenols, and calcium which inhibit it, the individual’s iron status is far and away the major variable affecting non-haem iron absorption. And the primary mechanism via which the body ratchets non-haem iron absorption up and down is…
Hepcidin, the master iron regulator
Hepcidin is a peptide hormone produced by hepatocytes (liver cells). It acts by binding to ferroportin, an iron transporting protein located on the membranes of cells in the duodenum (upper small intestine) and liver, and also on macrophages (white blood cells whose job is to engulf and digest pathogens, cancer cells, cellular debris and foreign substances… and worn-out red blood cells, from which they reclaim iron and return it to the bone marrow to make new red blood cells). The binding of hepcidin to ferroportin prevents these cells from releasing iron into circulation, thus lowering plasma iron levels and inhibiting iron absorption.
When liver iron stores and circulating iron levels4 are high, or when inflammatory markers rise, more hepcidin is released, reducing the amount of iron absorbed from food and directing cells to sequester iron. Conversely, when circulating iron and oxygen levels fall and the bone marrow needs to make more red blood cells, hepcidin release declines, permitting more absorption of dietary iron and causing cells to release stored iron into the bloodstream so that it can be utilised.
Thus, hepcidin helps the body maintain its iron level in the Goldilocks zone: not too little, not too much. It allows us to adapt to a change in iron status – for example, due to sudden blood loss or to taking a high-dose iron supplement – by rapidly altering the amount of iron we absorb. Likewise, it accommodates situations of increased iron demand, such as mid to late pregnancy, during which hepcidin release is naturally suppressed. And in periods of heightened inflammation it tamps down iron absorption and decreases the amount of iron in circulation, thus neutralising the pro-oxidative effect of iron in a situation in which oxidative stress is already increased, and decreasing the viability of iron-dependent infectious microorganisms. Finally, and very importantly, hepcidin also facilitates adaptation to a change in the proportion of haem and non-haem iron consumed in the diet.
It’s been known for decades that the adaptation to high or low iron bioavailability occurs quite rapidly – within 10 weeks, in controlled feeding studies in both men with normal iron stores, and women with suboptimal iron stores. More recently, a study comparing iron absorption in omnivores, whose diet contains both haem and non-haem iron, vs habitual vegans, whose diet contains only non-haem iron, found that the vegans absorbed a higher percentage of the non-haem iron from a test meal of pistachios (which contain iron absorption blockers including phytate and polyphenols), and that this greater capacity for non-haem iron absorption was associated with lower baseline levels of hepcidin in vegans than in omnivores.
Importantly, the vegans’ higher iron absorption occurred despite their habitual consumption of compounds in plant foods that reduce iron absorption. In fact, one of those compounds that has historically been labelled as an iron absorption blocker – phytate, or phytic acid – paradoxically increases intestinal iron absorption when eaten regularly, at least in part by reducing hepcidin levels.
The diet-gut-iron connection
Another major – and related – influence on hepcidin levels is the composition of the gut microbiome. Most of the bacteria that inhabit the human gut require iron for survival. And while we rely on a diverse array of bacteria to perform a myriad of functions that are crucial for maintaining and restoring our health, it’s also important to limit overgrowth of gut bacteria with virulence genes that are activated by iron availability – that is, bacteria that can multiply and cause disease if they obtain unabsorbed iron from food or supplements.
There is a bidirectional relationship between hepcidin and the gut microbiota. Pathogenic bacteria release inflammatory chemicals, including lipopolysaccharide, into the gut, triggering the release of hepcidin which then reduces the availability of iron to gut bacteria by sequestering it in cells, thus stymying bacterial function and reproduction. Hepcidin has been shown to inhibit the growth of Escherichia coli, Salmonella typhimurium, and Mycobacterium tuberculosis. Conversely, beneficial bacteria synthesise short chain fatty acids which reduce inflammation both in the gut itself and throughout the entire body, thus suppressing hepcidin release. These short chain fatty acids also enhance iron absorption.
Pathogenic gut bacteria thrive when there is an abundance of saturated fat in the diet, and little fibre – that is, a typical Western diet rich in the meat and milk of domesticated animals, and in refined carbohydrates. Conversely, a healthy plant-based diet rich in fibre and other microbiota-accessible carbohydrates, along with polyphenols, promotes the growth of gut bacteria that keep inflammation in check. And there’s even a genus of beneficial gut bacteria, the lactobacilli, that don’t have any requirement for iron because manganese takes the place of iron in their enzymes, and in fact enhance our absorption of non-haem iron by secreting lactic acid. We can boost our lactobacillus population by eating lactic acid fermented foods – including yoghurt, sauerkraut, kimchi and sourdough bread – and also by eating plant foods rich in prebiotic fibres and polyphenols.
Unfortunately, high-dose iron supplements, and iron-fortified foods, result in high levels of free iron in the gut, which can lead to pathogen overgrowth, intestinal inflammation and diarrhoea. That intestinal inflammation triggers hepcidin release. And the spike in serum iron and transferrin levels that occurs after taking an iron supplement also causes hepcidin levels to rise.
Just to make this point 100 per cent clear, taking an iron supplement causes your body to release a hormone which inhibits iron absorption from the subsequent meal, and it may also cause intestinal dysbiosis which results in that hormone being chronically elevated, such that your iron absorption rate is sub-par pretty much all the time. Bummer, eh?
So, what should a person with chronically low iron levels do? We’ll explore the answers to this surprisingly complex question, in Part 2!
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- Usually caused by either hereditary haemochromatosis or repeated blood transfusions, and less frequently by overconsumption of iron supplements. ↩︎
- Spelt ‘heme iron’ by our American friends. ↩︎
- Accounting for roughly half the total amount of iron in these foods. ↩︎
- Strictly speaking, when levels of transferrin, the protein that transports iron through the blood plasma, are high. ↩︎
