Inflammation

Inflammation can be good or bad – appropriate or excessive. Unless otherwise indicated, when used here the word “inflammation” means bad or excess inflammation – the kind that results in disease – not the kind that protects us from infections and assists in healing.

Good and bad inflammation are different but not unrelated. In fact all that might be required to turn ‘good’ inflammation into ‘bad’ inflammation is longer duration and/or greater intensity.

It’s often helpful to speak of turning inflammation “on” or “off” – so we’ll use those terms. But it’s important to realize that, in the body as a whole, ‘inflammation’ is a constantly ongoing process. How much constant, whole body inflammation is there? The answer, for most of us, is “too much.” The constant ‘background’ or ‘base’ level of inflammation can be referred to as the “baseline inflammation level” and the amount above what’s healthy can be called “excess inflammation.”

1. Inflammation is the cause of many ailments.

It is increasingly evident that excess inflammation is associated with the onset and progression of many ailments.

That’s a fact – but we’ll take the next step and say that  excess inflammation is the cause of many ailments. That might seem like a small step but it’s really quite big – because with that step we’ve moved from what can be observed (science/fact)  to conjecture and speculation – otherwise known as a hypothesis.

As we look at each condition or disease discussed on this site we’ll test each major hypothesis of this theory. It may be impossible to prove any aspect of the theory – but we can look at the evidence in favor and against to see whether that evidence is strong or weak – abundant or scarce.

Please keep in mind, however, that the theory is meant to be practical – not academic. The goal is to construct a basic model that can be tested and, as appropriate, used in developing a new and effective treatment for inflammation related disease (e.g. something that works.) Nothing against getting smarter – but the primary goal is getting better.

2. NF-kB is the inflammation Master Switch.

The NF-kB system (aka nuclear factor kappaB or NF-kappaB) is known to be a key regulator of inflammation. It turns on, and off, the genes that code for most of the critical elements in inflammation – so it effectively controls inflammation. That’s what makes it the inflammation Master Switch. And that’s why, just as inflammation has been found to play a critical role in many disease states, NF-kB is also being discovered to play a critical role. Excess inflammation and excess NF-kB activation go hand in hand.

While others may not refer to NF-kB as a “Master Switch” – the concept is hardly novel. The importance and centrality of NF-kB is well-accepted and widely recognized.

Skipping to the punchline – since inflammation is the key to so many ailments – and since NF-kB is the key to inflammation – if we can control/affect NF-kB we can control/affect a lot of different ailments. Effectively inhibiting NF-kB would allow us to effectively reduce inflammation, which could help a lot of people get better.

The possibility of effectively controlling NF-kB is not out of reach, because we possess the basic tools with which to achieve that. Natural NF-kB inhibitors are abundant, safe, and already in widespread use. Essentially every fruit and vegetable is, to some extent, a natural NF-kB inhibitor. That’s why eating more fruits and vegetables reduces the risk of cancer, Alzheimer’s, diabetes, arthritis, etc. – because they inhibit NF-kB and thereby reduce whole body inflammation.

What’s required in order to develop an effective new treatment from existing tools (the NF-kB inhibitors in fruits and vegetables) is simply to identify the best source and then properly deliver these already existing ‘drugs’. Drugs? Yes – drugs, chemicals, molecules, food – call these natural plant constituents whatever you wish. They are chemicals that affect your body. Vitamins are drugs. Caffeine is a drug. Sugar is a drug. We don’t normally think of them as such – but we could.

It’s usually the case that some sources of the natural drug are better than others. Vitamin C is found in beets and celery and apples and cod roe. But chances are you’ll reach for an orange, not fish eggs, when you want vitamin C. Caffeine is found in chocolate, but if you’re sleepy you probably don’t reach for a candy bar, you reach for a cup of coffee. Both choices make sense because oranges have lots of vitamin C and coffee has lots of caffeine. It’s the same with the natural NF-kB inhibitors. They are found in nearly every fruit and vegetable, but some sources are much better than others.

After having found a good source for the desired drug, it’s not uncommon for us humans to enhance the desired effect by manipulating the way it’s delivered. A cup of coffee might be fine, but if you’re really tired a shot of espresso might be better. Same caffeine drug – just more concentrated. Simple? Yes. Obvious? Of course.

But nothing is simple or obvious until you know what you’re looking for, and why. It may be ’simple’ and ‘obvious’ that you can treat or prevent scurvy with an orange. Yet hundreds of thousands died after suffering through treatments that ranged from drinking whiskey to blood letting – because they didn’t know what they were looking for or where to find it.

According to this theory, NF-kB is the inflammation Master Switch. So we’re looking for the most effective natural inhibitors of NF-kB. Given that, it’s relatively easy to identify the best source(s) and manipulate the delivery system to enhance the desired effect.  The goal is fast and effective relief from inflammation via the creation of a natural NF-kB inhibitor ‘espresso’.

3. Excess inflammation results from over-activation of NF-kB.

It’s a fact that NF-kB activation generally leads to inflammation. Again, the hypothesis is that excess NF-kB activation is the cause of excess inflammation. A bigger step – a leap actually – is the assertion that without excess NF-kB activation, there is no excess inflammation – at least not of the type associated with (causing) the inflammation related conditions – like autoimmune disease, asthma, osteoarthritis, migraine and others.

NF-kB is like the thermostat for inflammation. The degree to which NF-kB is activated determines the temperature (inflammation) in the entire building (body.) When NF-kB is ’set’ properly, everything is fine. When it’s set wrong, no amount of fiddling with the duct work will put things right.

Influencing NF-kB means influencing inflammation. Controlling NF-kB means controlling inflammation. No additional intervention is required. No additional knowledge is required.

It doesn’t matter why NF-kB is over-activated. The cause might be the smog in your city, a genetic vulnerability or a defect in some yet undiscovered pathway. It could be gremlins. It doesn’t matter. We don’t care.

That is the meaning of Master Switch as used here. And yes, it’s quite a leap.

But we need to take a leap or two if we’re going to end up with something useful – and we need something useful. The incidence of all conditions related to inflammation is rising dramatically – the cause is unknown and the treatment is elusive. So this theory is deliberately simple – testable – usable. To the extent it’s right, it gives us a tool that’s easy to use, safe and inexpensive. The fact that it might be wrong – even totally wrong and entirely without merit – is a virtue relative to an approach that is always so cautious and nuanced that it’s never very wrong, very right, or very useful.

I’m of the opinion that we’re in a war. If we could see all those around us who are suffering and dying it might fill us with a sense of urgency. Leaping might not be ideal, but the alternative is to wait until every detail of the immune system has been revealed. And that task won’t be completed in my lifetime – or yours. It’s the modern version of a Gordian Knot.

As you may recall, the Gordian knot was so complex that no one could unravel it. Moreover, it was foretold that whoever undid the knot would become ruler of all Asia.

Upon hearing that, Alexander the Great simply took his sword and cut the knot.

Alexander might have been a cheater – opinions vary – but let’s give him credit for recognizing an insolvable problem and finding an alternate solution.

The ’sword’ we’ll use to cut through the immense complexity of inflammation will be NF-kB. We’ll try to pin it all on excess activation of NF-kB – and basically neglect everything else.

But there won’t be any cheating. Just the opposite in fact. A very specific, simple hypothesis (like this one) is the most testable. So we’ll test it as each condition is discussed. We’ll defer entirely to the science and to the real scientists – those who labor at untangling the knot one strand at a time – those without whom even this simple theory would be impossible.

4. Over-activation of NF-kB is caused by an excess of NF-kB activators vs. inhibitors.

NF-kB is constantly being acted on by cellular and chemical messengers. Some turn NF-kB ‘on’ while others turn NF-kB ‘off.’

It is well-accepted that the balance between these two opposing influences determines the extent to which NF-kB is activated at any given moment. It follows that NF-kB activation results from a relative excess of NF-kB activators.

Again, according to this theory it doesn’t matter what those NF-kB activators are or how they arise. They are pro-inflammatory forces. That’s all that counts.

5. NF-kB is dependent on external inhibitors.

Most scientific investigation of the immune system has focused on the immune system itself, to the neglect of external influences – at least those external influences related to diet. This presents an incomplete picture, because those external influences are very important.

A number of phytonutrients have recently come under examination in relation to inflammation. In essentially all cases, beneficial phytonutrients are found to be inhibitors of NF-kB. On closer examination, even many of those phytonutrients previously valued as ‘anti-oxidants’ are found to act primarily via inhibition of NF-kB.

So the use of natural NF-kB inhibitors is neither harmful nor dangerous. It’s also not unusual. Quite the contrary – the use of external NF-kB inhibitors is beneficial and essential. Assuming you eat fruits and vegetables, you do it every day.

The human immune system was working just fine (more or less) when our diet included large quantities of fruits, nuts, vegetables and spices – all rich in natural NF-kB inhibitors. That is because the immune system evolved – or was designed – to function best when continuously bathed in dietary NF-kB inhibitors. Of course people still got sick – but we’ll get to that in a moment…

The precise means by which these natural NF-kB inhibitors act, and the full scope of their effect on the immune system, remains unknown. They do not appear to ‘knock out’ NF-kB function or ’slam’ the immune system in the same way a pharmaceutical might. It’s not possible to overdose on them – but a certain minimum level seems to be required for proper immune function. It might be that they somehow ‘cooperate’ with the immune system in the regulation of inflammation. Or it might be that they are selectively (actively) employed by the immune system when and as needed.

In fact these natural NF-kB inhibitors act very much like a vitamin: “a substance that is essential, in small quantities, for normal body function – a deficiency of which results in disease.” A better term for this diverse group of agents might be “vita-class.” Could it be that the immune system – and especially the body’s ability to turn off inflammation – stops functioning properly when there is a deficiency of this “vita-class”? I think so.

While it might seem odd – or unscientific – to suggest that natural NF-kB inhibitors ‘cooperate’ with the immune system, one recent publication demonstrated that curcumin is effective at inhibiting NF-kB (in the lining of the colon) only when a specific anti-inflammatory molecule produced by the body (IL-10) is also present. When IL-10 was not present, curcumin had no influence on NF-kB.

So when your body is acting to shut down inflammation in the gut – by producing IL-10 – curcumin comes alongside and helps shut it down. But once inflammation is relieved, and after IL-10 levels have dropped, curcumin just sits around doing nothing. That’s quite remarkable – and sounds very much like cooperation. The scientists who discovered this interaction called it “synergy.”

I suspect there are a great many such complex and surprising interactions going on between natural NF-kB inhibitors and the immune system. Of course the vast majority of these interactions will probably remain undiscovered for some time. Curcumin just happens to be one of the most well researched of the natural NF-kB inhibitors. So we know a lot (but not nearly all) of what it does and how it does it (basically by inhibiting NF-kB.) But from just what we know so far, the scope of activity, and benefit, delivered by curcumin is simply staggering. And it does what it does without a single known side effect.  I’ll repeat myself here – because it’s easy to miss just how remarkable this is. It changes your body in such a way as to produce a beneficial effect in the treatment of dozens of different diseases without causing any side effects – zero – none.

If I had designed a drug that did all this, and that had no side effects, I would be sitting at home waiting for a call from the Nobel committee. But since someone else designed it, it goes unrecognized.

But curcumin probably isn’t all that special. It looks special because it’s been extremely well studied.  If  the other NF-kB inhibitors were to be extremely well studied, then they might look just as special. That’s not to say that some NF-kB inhibitors are not better than others – some are. But curcumin per se is not required to achieve the long list of beneficial effects shown above. What’s required to achieve those effects, I believe, is a sufficient quantity and proper assortment of NF-kB inhibitors.

An assortment of NF-kB inhibitors is preferred because each acts in a slightly different way and because, in addition to synergy with your immune system, they can be synergistic with each other.

We can speculate on their various actions, but what’s clear is that your body relies on these natural NF-kB inhibitors for proper immune function – especially for the ability to properly shut down inflammation. That should be no more surprising than our reliance on bacteria for proper bowel functioning. Our guts have spent a long time with the bugs, and we’ve come to rely on them. Our immune system has spent a long time with natural NF-kB inhibitors, and we’ve come to rely on them. It would actually be quite odd if your body was not reliant on them – or if suddenly removing NF-kB inhibitors from your system didn’t have an adverse effect on health.

6. Lacking sufficient external inhibitors, NF-kB is chronically over-activated.

Over the course of the past 50 years, those of us in the Western world have done a very good job of eliminating from our diet the vast majority of natural NF-kB inhibitors. In addition to eating fewer fresh fruits and and vegetables, those we do eat often contain lower concentrations of NF-kB inhibitors, which tend to be slightly bitter. Modern produce often has this ‘bitterness’ bred out – we all want the sweetest apple.

By removing NF-kB inhibitors from our diet, by whatever means, we have shifted the balance in favor of inflammation (NF-kB activation.) We have, at the very least, removed the essential anti-inflammation buffer that natural NF-kB inhibitors provide. We’ve radically altered the activator/inhibitor balance by yanking out all the inhibitors. As a result, our baseline inflammation level becomes excessive. We have BILE: Baseline Inflammation Level Excess (clever, eh?)

The shift in favor of inflammation would be pronounced even without the addition of more NF-kB activators – but we have added plenty. Our modern lifestyle subjects us to an enormous number of pro-inflammatory, NF-kB activating influences. Stress, auto exhaust, a ‘fast food’ diet, environmental toxins, high fructose corn syrup, tobacco, obesity, and many other factors common to our daily routine are potent activators of NF-kB.

So we’ve shifted the balance on both sides of the equation: far fewer NF-kB inhibitors and far more NF-kB activators. Is it any wonder the incidence of inflammation related disease is skyrocketing?

Call it what you will – BILE, chronic inflammation, systemic inflammation, sub-acute inflammation or silent inflammation. All refer to the same phenomenon – a smoldering, ongoing, low-grade inflammation that increases the likelihood of eventually developing Alzheimer’s, certain forms of cancer, and osteoarthritis – increases the likelihood of developing an autoimmune disease – increases the frequency and severity of acute inflammation attacks such as with asthma or migraine – increases the frequency and severity of neuropathic pain and other forms of chronic pain – and that in fact results in accelerated aging.

7. Supplementing external inhibitors results in optimal function.

By supplementing external NF-kB inhibitors, the imbalance between inhibitors and activators may be corrected. The over-heated immune system can be cooled down – because NF-kB is once again able to function normally. It’s performance is optimal. It can turn on. It can turn off. It is not constantly ’stuck’ in the on position – so it does what it naturally wants to do – which is to turn off once inflammation is no longer needed.

The anti-inflammation buffer that NF-kB inhibitors provide may be re-established, and with it the normal threshold for (full-blown) inflammation. The ‘hair trigger’ inflammation response is eliminated (e.g. no more migraines.)

The function of certain anti-inflammation mechanisms may be restored – especially those involved in turning inflammation off, as per the curcumin example.

The problem is, correcting the imbalance may require a lot of those natural NF-kB inhibitors. (And this is no doubt why the value of natural NF-kB inhibitors has remained largely unrecognized – because unless you supplement with a sufficient amount, in the right blend, given by the right method, the effects often appear as mild to none.)

If you believe that we should be eating like chimpanzees, that would be a diet consisting of about 95% fruits, vegetables and roots – all fresh, wild and raw of course. (And a diet like that has been shown to help.) But even if you think we ‘only’ need to emulate the NF-kB inhibitor/activator balance our grandparents had, that also might be quite a challenge.

At least it would be for me, since I’m starting deep in the hole. I live in a city, drink fluoridated water, use household chemicals, have a rather sedentary job, use plastic, sleep too little, etc.  Even if I eat like grandpa did – even if I eat like a chimpanzee – I’ll need more NF-kB inhibitors to counter the effect of all those NF-kB activators. I should start by eating better, but I’ll probably need more NF-kB inhibitors than I can reasonably get from my food. Besides that – what would I eat?

The government thinks they are helping us. The USDA now recommends that every adult male consume 9 (yes, 9) portions of fruits and vegetables each day (and at least two of the vegetable servings should be dark green or deep yellow.) It is estimated that less than 1% of all men comply with this recommendation on a routine basis.

That’s not ‘bad’ advice – it’s just not as helpful as it could be. Some fruits and vegetables have far more NF-kB inhibitors than others – just like some fruits and vegetables have much more vitamin C than others. If you don’t know what you’re looking for you might eat a lot of vegetables and still get scurvy. If you know, you eat one orange and you’re fine.

I need to know more than what the USDA tells me because I’m starting off in the hole. First I need to eat enough NF-kB inhibitors to counteract the effects of modern city life. Then I need to eat the historically ‘normal’ amount – emulating either grandpa or the chimp.

But even assuming I can do that, it still might not be enough, because I might already be suffering the effects of an inflammation related condition. If I already have arthritis, or fibromyalgia, or migraine – or any genetic predisposition to inflammation – I’ll probably need still more NF-kB inhibitors – because the disease or the genetic vulnerability is slamming me with yet more NF-kB activators.

Then again, maybe I won’t need more.

8. Optimal function may result in the elimination of inflammation or a reduction in its severity.

The immune system is exceedingly complex, and is characterized by multiple feedback loops. The purpose of these multiple feedback loops is to ensure that inflammation (full-blown inflammation) turns on when required – not accidentally – and that it turns off once it is no longer required. Double and triple redundancy is meant to protect against the possibility that a single aberrant signal triggers (or terminates) a full-blown inflammatory response.

The result of chronic NF-kB activation may be to ’short-circuit’ some of these protective mechanisms. Without the anti-inflammation buffer, the immune system probably becomes exquisitely sensitive, such that even a minor pro-inflammatory stimulus results in the launch of what is an excessive immune response. For anyone genetically predisposed to migraine that will mean more migraine attacks. Or if you’re predisposed to lupus/Crohn’s/asthma – worse exacerbations and more attacks.

By restoring optimal function to NF-kB it may be that those minor pro-inflammatory stimuli are no longer be sufficient to trigger an attack. The ‘disease’ is not ‘cured’ – the genetic predisposition remains – but if no inflammation develops – well – that is a good outcome.

And what if inflammation does develop – or never resolves – because a disease is slamming more NF-kB activators into our system? Then we’ll do what people have historically done and slam right back with more NF-kB inhibitors.

As previously alluded to, even our ancestors (both ancient and recent) got sick . Sometimes it wasn’t enough to live in the jungle, exercise all day and eat a fruity, nutty, leafy diet.  What did they do then?

They reached for plants that were especially effective in treating inflammation – plants like turmeric, ginger, sunflower, dandelion and others. As it turns out, many of the plants used in traditional medicine are especially effective NF-kB inhibitors.

Since we’re already so far in the hole, and since we already have who knows how much inflammation smoldering in our heart, joints, blood vessels and brains, we need to reach for these especially effective NF-kB inhibitors right away. That’s even more the case if we’re already sick.

Using very effective NF-kB inhibitors, in sufficient quantity, should work – always. Because in theory it doesn’t matter what’s causing the excess activation of NF-kB. In theory we don’t care. In theory we can extinguish any inflammatory fire by dumping enough natural NF-kB inhibitors on it. That’s the theory.

The truth is we don’t know to what extent natural NF-kB inhibitors can counteract certain especially powerful pro-inflammatory forces. Add the fact that some individuals respond differently than others – as is always true – and our ability to predict the extent of success in any given case declines. Though some things work extremely well, nothing works perfectly, for everyone, all the time.

What we do know, however, is that correcting the deficit in natural NF-kB inhibitors makes sense as either a first step, or a step to be taken in conjunction with whatever other treatments are employed in the fight against inflammation. Failing to address the deficiency in natural NF-kB inhibitors makes no sense at all. It’s unlikely the best results will be achieved by leaving one source of inflammation unchecked while treating another.

9. NF-kB is not fundamentally broken.

Essential to the theory is that NF-kB, while it may not be functioning properly, is not fundamentally broken. If NF-kB is ‘broken’ – if it’s not responsive to the balance between inflammation activators and inhibitors – then adding inhibitors is just a waste of time.

If NF-kB were fundamentally broken, one might expect to find evidence of that in autoimmune disease – since autoimmune disease is generally considered the most severe form of inflammation (e.g. versus atherosclerosis, osteoarthritis, etc.)

What we find when observing the course of a typical autoimmune disease suggests just the opposite – that neither NF-kB, nor the immune system as a whole, is fundamentally broken:

• Autoimmune disease is characterized by ‘flares’ and remissions. During remission it may seem as if the disease is entirely gone. How would that be possible if NF-kB, or the immune system, was fundamentally broken?

• If the body recognizes self as foreign and attacks – why does it not entirely destroy? Transplanted organs that are rejected as foreign are completely destroyed within days or weeks. There is no remission – ever.

• The auto-antibodies found in autoimmune disease are not a principal cause – and can even be misleading. Some people have lots of auto-antibodies and no disease. Others have few auto-antibodies and have disease.

• When one identical twin has an autoimmune disease, the other – with identical genes – often has no disease. The immune system is not genetically broken. Susceptible, yes – but not broken.

While beyond the scope of this overview, each of the above features of autoimmune disease can and will be explained in reference to the theory.

Likewise, both the theory and clinical trials that have been performed to date suggest that administering natural NF-kB inhibitors to those with autoimmune disease results in:

• more frequent and longer lasting remissions
• less frequent and less severe exacerbations

10. The theory is testable.

The theory can and will be compared with and tested against what is known about each inflammation related disease.

The following will be considered evidence in support of the theory:

• The disease is associated with inflammation.
• The disease is associated with excess NF-kB activation.
• There is evidence that inhibiting NF-kB is beneficial in the treatment of the disease.
• There is evidence that natural NF-kB inhibitors are beneficial in treating or preventing the disease.
• A defect or vulnerability (especially genetic) specific to this disease results in excess NF-kB activation.
• There is an explanation for the cause and progression of the disease that is consistent with the theory.