It’s the time of year for good intentions. That hand-knitted Christmas sweater from your Aunt Mildred, or another batch of dodgy mince pies from your Grandmother. All done out of kindness of course, but perhaps missing the target. Even if the jumper does have bells on it.

At this time of year, we also apply that same blind sense of kindness to our immune system. When we fall sick, our natural reaction is to bolster our defences by downing supplement pills by the handful. In our mind we’re the saviour of the battlefield – parachuting supplies directly to our frontline.

In fact, our supplement surge may be doing more harm than good. The battlefield isn’t as simple as we imagine – we know that our body is busy using amazing weapons to clear out invaders (*cough* my last post…), but this is just a small part of a grand strategy that’s swinging into action.

“It is best to win without fighting” said General Sun Tzu. With the invading pathogens competing with us for critical nutrients, our bodies start a war over resources, aimed at starving the enemy out and crippling its spread.

So next time you’re ill and reach for the supplements bottle, remember – the Iron Curtain has descended. Let it do its work.

A Strategic Reserve

This war for resources is called Nutritional Immunity, and iron is probably the best-known participant. This is for a good reason – iron is one of nature’s most powerful chemical magicians. Without dredging up too much Secondary School chemistry, it’s the ability to exist in different oxidation states that makes iron so useful to living organisms.

You can find iron at the heart of countless biological process – powering vital enzymes and dutifully carrying oxygen around in our blood. With iron in hand, cells can carry out incredibly complex chemical changes which would otherwise be virtually impossible.

Despite its importance, we don’t actually have that much iron in our bodies. Estimates vary – but most researchers agree you could make a medium-sized nail from each one of us (about 4g). Calculating the exact amount of pure elements (including others, like calcium) is quite hard, and previous work has relied on chopping up bits of cadavers (including grinding up bones in a pestle and mortar) and looking at what the mush held. Science is pretty glamorous at times.

An Insoluble Problem

Four grams seems pretty frugal considering iron is incredibly abundant in the world around us. The problem stems from those oxidation states mentioned earlier – the most common form of iron in nature is one which hates dissolving in water. As we’re mostly water, and carry out all our chemical reactions dissolved in the stuff, we’re left in a tight spot.

And we’re not the only ones. Unsurprisingly, iron is also a key resource for bacteria. One of its many uses is for replicating DNA, something which human cells due relatively infrequently, but bacterial cells can do every 20 minutes. For them, iron is absolutely critical to being able to grow.

So during an infection, when growth is everything, iron is in high demand. In response, your body moves into lockdown mode – rapidly hiding any spare iron and trying to starve the attackers into submission. The Iron Curtain has descended.

This lockdown state is called hypoferremia. Spare iron is quickly relocated to the liver for safe-keeping, whilst special white blood cells patrol our tissues scavenging any remaining loose iron. With hypoferremia in place, levels of available iron plummet, hopefully containing the bacteria long enough for the immune system’s cavalry to arrive.

But this is only the start. Bacteria arrive with a whole raft of tricks to extract what they need – they intend to turn to theft, stealing iron from the very host they’re infecting.

Running the Blockade

The primary bacterial weapon is a class of small molecules called siderophores. These are a team of scavengers with an unbelievably strong ability to root out iron, even in the most barren of landscapes. Manufactured in the bacterial cell, they are sent flooding out into the nearby tissues and forage whatever iron they can find, before being picked up again by the mothership. The iron they captured is then released for use, and the siderophore recycled.

A Ferrous Wheel

Looking through a list of siderophores is like describing a doctor’s worst nightmare – vibriobactin from Cholera, yersiniabactin from Plague, alcaligin from Whooping cough, mycobactins from TB, aerobactin from the dysentery bacterium. Having a siderophore is a mark of prowess – by overcoming the iron bottleneck, a feeble enemy can transform into a monster.

The use of these siderophores has sparked an immune arms race – with our body manufacturing compounds which target and inactivate these scavengers as they are out foraging. In response, some very dangerous bacteria such as anthrax have turned to undetectable “stealth” siderophores which can still run the blockade (rumour has it, they can make the Kessel Run in less than 12 parsecs). Even piracy is on the cards, with bacteria stealing scavenger compounds sent out by competing pathogens. This is an all-out skirmish.

Good Intentions, Bad Consequences

Sadly the complexity of this battle, and the dangers of wading in with supplements, have often been learnt the hard way.

With iron supplements being cheap and easily transported, they have been the focus of several large studies aimed at improving the health of nutritionally-deprived communities across the world. One large trial in Zanzibar revealed a significant spike in disease after iron supplements were introduced. Further research has shown that the sudden influx of iron can reactivate hidden, dormant infections like malaria and TB which have been waiting for their big break. With the removal of the iron bottleneck that previously constrained them, they sweep to victory over their weakened host.

Gathering Intelligence

Understanding the balance of resources is about understanding the challenges facing an individual’s immune system. This appears to be true not just for iron, but for zinc and manganese too. When we have a cold, we often go looking for a fast fix – but large doses of supplements aren’t the answer. We’re blindly messing with an equilibrium that is already trying to deliver the best outcome.

The same is likely to be true for long-term supplements that haven’t been prescribed by a doctor. Only this week, the Annals of Internal Medicine published several papers which showed that long-term supplement regimes had no useful outcome for brain health (article, free patient summary) or heart attack recovery (article, free patient summary). They were quite clear in their editorial – “we believe that the case is closed— supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful.”

These trials are huge and span several years, but ultimately tell us something we probably already knew – a pill won’t magically fix things. If we want to help ourselves, either in the long-term or short-term, the best advice is to eat a balanced diet from which your body can extract the nutrients it needs and wants. Playing with the system artificially can make it easier for your body to get hold of things like iron, but will also make it easier for bacteria to intercept it.

Knowledge is Power

Nutritional immunity is a growing field of research – but one which offers some exciting opportunities for knowledge-led intervention. The research that has pieced together these iron-scavenging pathways is opening up some promising vaccine targets, whilst targeted probiotics have demonstrated great potential for hindering dangerous bacteria, through competition for iron.

We might not have a quick fix, but we do have a highly evolved immune system on our side. It was locked into this arms race back when we still ate things out of each other’s fur, and time has honed it into a strategic mastermind. Even now we’re only just starting to understand its tactics, and we’re being surprised at every turn. So, until we know a little more about what’s going on, perhaps its best is we just sit back, eat our vegetables, and let it do its amazing thing.

If you really HAVE to help, you could always don that lovely, warm sweater from Aunt Mildred…

Merry Christmas.

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