Chronic Inflammatory Conditions: How Cortisol Actually Works
Why It Depends on the Mitochondria (and Where Licorice, Adaptogens and the Organic Acids Test Fit In)
TLDR:
Cortisol is the primary anti-inflammatory agent in our bodies, but depends on the mitochondria to deliver this effect
Long-term stress reliably results in a loss of cortisol activity, an increase in nitric oxide and hypoxia at the mitochondria
Interventions must target both cortisol activity and the mitochondria to resolve inflammation (and not forget baseline stress)
Mitochondrial activity can be measured with an Organic Acids Test
Chronic inflammation is a central factor in almost every long-term health challenge. This can manifest as ‘classic’ inflammatory issues, like asthma, joint pain or rashes, but can also drive mitochondrial issues, insomnia or mood challenges. While the symptoms can therefore vary from one person to the next, the one factor that binds these chronic conditions is how the inflammatory activity is resistant to ‘standard’ anti-inflammatory therapies. Aspirin won’t cut it.
A Self-resolving Process… Normally
Western medicine is underpinned by a one-pill-for-every-ill model, a paradigm that assumes that there is a solution for any given medical problem. This is central in why Western medicine fails in complex/chronic disease (and also why there is such little interest in research into such conditions), as changes are only feasible when we take time to understand the central mechanisms that are regulating the processes that result in the chronic inflammatory state. That’s processes (plural).
In such states, the inflammatory apparatus is responding to the signals it's receiving on multiple levels. There are a lot of ways that the immune system self regulates – so-called ‘resolvins’ that include cannabinoids, endorphins, lactate, and adenosine - and the activity of these systems can vary from one person to another (and will change at different phases of the inflammatory response). However, there are two systems that a) have been dysregulated in every case that I've ever looked at, and b) have permitted improvement in every case I've worked. These are cortisol and energy metabolism.
So it's of great interest that a recent study has helped to delineate the interaction between these two critical systems. Specifically, how cortisol affects energy metabolism in an especially crucial way to turn off unwanted inflammation.
Self-resolution Depends on Itaconate
First, let's take a look at how the cortisol-driven process should work, and then we'll take a look at how problems occur in individuals who are suffering from these problems. When all is working well, the body produces both cortisol and upregulates an enzyme to form a very specific energy metabolite called itaconate. itaconate is crucial to the behaviour of the immune system as it blocks pro-inflammatory signals in activated immune cells called macrophages, which are the resident immune that act as resident sentinels (and are tasked with providing both surveillance and also initiating inflammatory responses).
Upon encountering a perceived threat and initiating an attack, itaconate production is simultaneously increased in the mitochondria, where it directly inhibits the metabolic activity of pro-inflammatory immune cells, but also accumulates in the cytosol (the watery, ‘central’ area of the cell) and initiate a whole host of anti-inflammatory effects; which include activation of the antioxidant/NRF2 response, and turning of the NRLP3 inflammasome. It also polarizes immune cells towards the anti-inflammatory M2 type (ref). The accumulated itaconate essentially ‘stands by’ until, as soon as the threat is resolved and the acute inflammatory stimulus wanes, there is a ready-made impetus to reduce inflammatory activity and, as a consequence, restore the body to homeostasis.
However, things can go wrong when the threat is not resolved quickly (which is a separate discussion, but ultimately comes down to insufficient permission that's provided to the immune system to run at full speed, a problem that itself is driven through poor energy security). In these cases of unresolved threats, we see that the diversion of energy towards inflammatory activity can have an unwanted impact on the mitochondrial energy production. This wouldn't normally be a problem if it's only a temporary thing. But when it is sustained past a certain threshold (which, depending on pre-existing stress burden and metabolic resilience, could be a matter of weeks but could sometimes be extended to years), we see a problem whereby the conditions at the mitochondria become disturbed (although there are other mechanisms, this is primarily due to stress-induced endotoxemia and impacts on cortisol receptors, with downstream impacts on nitric oxide production and mitochondrial activity). This means that there is no longer enough mitochondrial activity to produce the itaconate that's required to turn the system off. Consequently, the ‘brakes’ of the immune system have become disabled. What’s worse, we now see dysregulation, whereby there isn't enough energy availability to win the war, but neither is there enough to produce the itaconate needed to stop the fighting.
Ongoing activation of the immune system ensues (via the endotoxemia mechanism, noted above, as well as through changes in vagal tone and increased mast cell activity). Increase immune activity results in an ongoing drain in our central energy stores, necessitating increased stress responses in compensation, leading to a self-perpetuating cycle. Inflammatory symptoms, which will vary from one person to the next, accompany this pattern. This is where the importance of itaconate status cannot be downplayed, but it's also where we need to consider the role of cortisol.
This recent study outlined the vital importance of cortisol in stimulating the itaconate formation. Without sufficient cortisol activity, itaconate levels remain suppressed, a further obstacle in the situation that we've outlined. This is especially important because a universal feature in these chronic inflammatory states is long term stress.
Role of Long-Term Stress
Stress is ultimately any circumstance where energy needs do not match the perceived energy requirements. And the stress response is launched to bridge this gap by releasing energy into the circulation. However, noted above the stress response itself becomes dysregulated when overused. This centres on the role of cortisol receptors, which are unfortunately down-regulated whenever endotoxins, little fragments of dead bacteria can gain access to the circulation (ref). This process happens as a direct consequence of the stress response, due to the stress induced opening of channels in the gut lining, done so to gain access to sugars and salts (with the cost being that these little fragments can also gain access).
It's extremely relevant that when cortisol can't do its activity, we will see a host of problems, ranging from blood sugar level dysregulation to a reduced ability to tolerate stress. We may also see problems with blood pressure, hydration, and sleep/wake cycles and well as increased basal adrenaline levels. But it's the control of inflammation that tends to cause the biggest costs in the picture we are discussing here.
(Side note: cortisol is so often misunderstood due it being labelled ‘the stress hormone’ and how it is reliable higher in a whole hole of disease states; see this article for why cortisol is not actually bad and plays a vital protective role in stress- and inflammation-related issues).
Meanwhile, this new research paper tells us why cortisol is so important and how it does its job. If you have insufficient cortisol activity, you will have insufficient itaconate formation and insufficient control of the inflammatory process. This centres on a cortisol-responsive enzyme called aconitate decarboxylase 1 (ACOD1) which forms the itaconate from aconitic acid.
Although not discussed in this paper, it is worth pointing out two things:
- 1. What we get from an enzyme never just relies upon the activity of the enzyme itself, but also on the availability of the starting product
- 2. The starting product here is aconitic acid which declines in states of inflammation-induced hypoxia (something that becomes inevitable when cortisol activity wanes, and excess nitric oxide creates competition with oxygen).
In short, a lack of cortisol activity hampers both the supply of aconitic acid and the activity needed to convert it, a double whammy.
Readers of this article may naturally form the conclusion that all we need do is increase the cortisol activity and as a result, we will regain control of the inflammatory process. This is partially true and there are a number of anecdotal reports of individuals seeing improvements from short-term steroid treatment. However, the use of steroid medications risk a direct down-regulation of cortisol receptors, which means they either become ineffective over time (even more ineffective!), or a higher dosage is required (something that can result in disturbances in the HPA axis and extreme difficulty when it comes to removing the medication).
Itaconate itself is not likely to be of use as an intervention, as it is so unstable (and analogs that have been deployed in research tend to produce unwanted side effects).
The scenario therefore screams out for a way to increase cortisol activity back to desirable levels without the downregulated of receptors.
Licorice Root and the ‘Adaptogens’
Enter Licorice Root. This is a herb that has played a central role in Traditional Chinese Medicine for at least 1000 years and is the most prescribed herb in in Ancient Egyptian, Roman, Greek and Chinese medicine and has demonstrated impressive anti-inflammatory effects in trials. It contains an array of plant chemicals but the most powerful component is glycerrhizinic acid, which inhibits an enzyme called 11b-hydroxysteroid dehydrogenase (11b-HSD). Why is this action so important? Because it would otherwise deactivate cortisol inside cells. Inhibiting this enzyme avoids such deactivation and means that the cortisol activity is increased. Most importantly, we do not see a downregulation of receptors over time.
The benefits of Licorice aside, we can also expect benefits from providing herbs that have been traditionally called ‘adaptogens’ for their impact on stress. The mechanisms of these herbs have since been investigated, and shown to impact at various roles in the HPA axis and on cortisol. They can be of great use in these scenarios. Here’s a brief low down of how they work:
- Korean ginseng. Demonstrates powerful effects in regulating nitric oxide, a gas that can have positive effects in supporting circulation but can cause cellular dysregulation when released in excess (as is the case in chronic inflammation). It is particularly relevant that it directly activates cortisol receptors.
- Ashwagandha. As well as having a pro-GABA effect (relevant as GABA is the primary calming neurotransmitter in our brain), it also increases cortisol activity by promoting increased cellular activity of the cortisol receptor (increased transcription at the nucleus of the cell). This increasing cortisol’s effects, particularly in regards to anti-inflammatory effects.
- Rhodiola Rosea. Well known for its ability to enhanced dopamine and protect dopamine neurons (doing both through inhibiting MAO-B, an enzyme that simultaneously breaks down dopamine and drives oxidative stress), it has also been shown to upregulate the expression of genes that produce cortisol receptors and increase binding efficiency (with the latter effect biased towards zone of the prefrontal cortex and hippocampus, particularly beneficial for the mood- and cognition-related effects of stress).
- Siberian Ginseng (aka Eleuthero). Not a ‘true’ ginseng due to the absence of ginsenosides, hence laws in the US outlawing the use of its common name, this plant contains steroidal glycosides that have similar properties in that they directly bind with glucorticoid receptors. Eleuthero has has also been shown to support metabolic health (by enhancing AMPK activity) and help stabilize mast cells.
The effects of these herbs are complementary, meaning that they can be used alongside one another. Their varying profile of additional benefits allows for a custom blend to match the needs present in each individual.
Bringing It Together & Taking Action
It is especially interesting to see this relationship outlined, as it helps explain why LIcorice has been so helpful over the course of millennia in long-term conditions. It also helps explain the patterns we see on the front line, whereby we can expect little improvement without shoring up cortisol activity.
However, such frontline patterns implore us to recognize the powerful role cortisol support can play in these circumstances, but also to maintain focus on the big picture, with focus on two other important areas: the stress response and energy metabolism.
When we speak about the stress response here, we are focused on the ‘upstream’ aspects. That is to say, the extent at which the stress response is deployed, aka How Stressed We Are. Management of the stress response is important to limit the pattern discussed above (that of the opening of the gut lining and the subsequent flood of endotoxins that have such undesirable effects at cortisol receptors) but also on its impact on energy security; it can be rightly said that energy metabolism governs everything, but autonomic function governs energy metabolism (and can determine if the mitochondria receive the permission they require to work, with thyroid status, adrenaline and sympathetic nervous system supply all key mechanisms through which this control is exerted).
In short, we can expect these herbs to help with regulation of the stress response, but not replace the call to assess factors that activate the stress response in the first instance.
We must therefore consider causes of stress, which can be conceptualized as a balancing act between energy availability (itself determined by energy production, energy signalling (eg. insulin/thyroid/etc) and energy theft from inflammatory activity) and perceived energy demands (themselves determined by daily workload, cortisol control/feedback of the HPA axis, and perceived needs for readiness (a complex but important area in itself, which involves a deeper diver into our learnt reflexes to environmental stimuli as well as the neurotransmitter balance that conveys such signals into the ‘alarm centres’ of the brain).
This is where, while we have already spoke in depth about the way that stress can drive endotoxemia and excessive nitric oxide production (which leads to hypoxia in the mitochondria), it is also important to consider how poor mitochondrial activity can leave the system under stress. I am speaking here about mitochondrial contribution to energy availability (and therefore energy security, outlined above, impacting on functionality of the entire system) but also in the local effect at each macrophage, where we have established that sufficient energy metabolism is required to maintain itaconate production.
While we’ve established that sufficient cortisol activity is necessary to maintain energy flux in macrophages, it is naïve to expect this to be the only bottleneck in energy production. Various mitochondrial enzymes require co-factors (such as B vitamins, Magnesium, Carnitine, Co-Q10) in order to function in an optimal fashion.
Equally, uncontrolled oxidative stress is known itself to inhibit the PDH enzyme in the mitochondria (required to effectively process glucose) as well as the electron transport chain (the ‘conveyor belt’ that moves energy compounds into the ‘furnace’ so that they can be converted into human energy, via combustion with oxygen). Additional support for the antioxidant response (or limiting exposure to factors that may overwhelm it, such as mould) are obvious steps, while Curcumin may also play a role here.
Recognizing that poor mitochondrial function leaves the body with low energy status (and therefore in a state of stress) and that poor cortisol activity is by no means the only factor in limiting mitochondria activity, we are left to consider:
Are there any nutrient shortages and/or dysregulated oxidative stress playing havoc with efficient production of energy?
How can we measure this?
There are a number of tests available to help answer this second question, although I would always recommend starting with an Organic Acids Test. This is a urinary test that measures around 75 metabolites formed in different zones of the body. While this gives us a great snapshot of various obstacles that a particular individual may be facing, it includes a number of markers to measure oxidative stress and glutathione production. Importantly, it also provides markers that outline where blockages may be occurring in the mitochondrial pathways (and, as a result, identifies what nutrients may be short or what steps may be called for).
Connecting the Dots – on the High Cortisol Needs of ‘Unexplained’ Conditions, Including Long COVID
The adrenal-inflammatory link is well laid out and I’ve seen reliable results in a whole host of conditions when ‘working backwards’ to identify and tend to the factors that influence both sides of this relationship in any given individual. This has been the case in the ‘unexplained’ conditions as well as autoimmunity, POTS-type patterns, mast cell issues, ME/CFS and, of course, ‘adrenal fatigue’.
In recent times, it has been useful in applying the same focus to those experiencing chronic challenges after viral infection; that which we tend to call ‘Long COVID’. I mention this for two reasons.
One is that ‘Long COVID’ features all the fundamental patterns of self-perpetuating patterns that I describe above (insufficient energy metabolism to maintain itaconate, which leads to ongoing immune activation and energy depletion, itself sustaining the poor energy metabolism but also driving the stress response into overdrive, with the resulting endotoxemia and down-regulation of cortisol receptors a further factor that compromises this energy metabolism and therefore itaconate… less control of the immune system, and more ongoing action, and so on and so on).
The second is the adrenal-specific features of viral infection. In the face of viral infection, the human body is actually designed to temporarily downregulate cortisol activity. It does so in order to provide a window through which the immune system can be especially active in order to better win the battle against infection. And this process works well, providing successful eradication occurs.
However, there can be some intended consequences of this response. The ‘temporary’ suppression can become more sustained if the victory is not won as swiftly as expect (again, consider the permission that the autonomic nervous system provides to the immune system, a direct consequence of energy security), which would quickly see these self-perpetuating cycles kick in.
Just as important is the way that some individuals whose systems are subject to high stress burdens will respond when their cortisol supply is interrupted; if the stress and inflammatory burdens were only being kept in check by a generous, round-the-clock supply of cortisol, we will see a quick emergence of those symptoms alongside the metabolic disturbances that come with an unchecked stress response and raging inflammation. This means that the virus can be cleared but leaving behind it the self-perpetuating cycle described above (one that centres on over-activation of the stress response, ongoing movement of endotoxins to circulation that, via their effect on receptors, drive a ongoing lack of cortisol activity) and is also explains why 100% of the case histories of ‘Long COVID’ show a high stress burden before viral infection shifted them into a state of dysregulation (note: one means through which authorities attempted to create fear was to point to how many athletes were affected, without ever considering the context of how, by definition of high-end training that purposefully pushes them to their limits, this group are subject to substantially higher stress and therefore have a much higher need for ongoing cortisol action than a typical member of society).
Of course, there are strong parallels between the physical burden experienced on a regular basis by competitive athletes and the cognitive energy demands that office workers place on their system in our productivity-obsessed culture. So too the round-the-clock activation of the stress response in individuals whose alarm systems have not received the nurture needed to relax appropriately (more common than not in our crumbling, emotionally-aversive, look-anywhere-but-inside society).
Summing It Up
- if we do not recognize the effects of supporting cortisol (and the importance of doing so) in controlling inflammation and maintaining the conditions needed for healthy energy metabolism, we leave individuals vulnerable to metabolic chaos whenever sustained stress (or viral infection) knocks out healthy cortisol activity.
- If we do not recognize that the relationship between cortisol’s effects and energy production goes both ways – as so elegantly shown in this latest research paper – we leave ourselves limited in our ability to fully leverage this key support.
- If we continue to ignore societal and psychological wellbeing and how it obligates round-the-clock cortisol activity as our last line of defence against metabolic chaos, it is inevitable that having chronic inflammatory conditions would become more common than not. Such a scenario would be barely conceivable, except for the fact that we are already there. The figure is 60%. It needn’t be.
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