Facilitated

8| High Cortisol Meets Chronic Inflammation: Decoding The Paradox

• The Facility Denver • Episode 8

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Dr. Mitchell Rasmussen explores the paradoxical relationship between high cortisol levels and persistent inflammation, breaking down the complex feedback loops that keep many patients trapped in chronic stress and inflammatory states.

• Cortisol is designed to be anti-inflammatory but often fails when stress becomes chronic
• Body inflammation leads to brain inflammation, creating a self-reinforcing cycle
• Poor receptor response to cortisol occurs despite high blood levels
• Vitamin D deficiency contributes to cortisol resistance through receptor dysregulation
• Mitochondrial dysfunction prevents cortisol from performing its anti-inflammatory role
• Brain inflammation reduces vagal nerve tone, increasing gut inflammation
• Identifying personal inflammation triggers is essential for breaking the cycle
• Simple interventions like proper chewing activate the vagus nerve and reduce inflammation
• Addressing nutrient deficiencies supports proper nervous system function
• Removing inflammatory foods is often the first step while waiting for comprehensive testing

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Stay curious, stay proactive, and we’ll catch you next time!

Speaker 1:

Welcome to Facilitated, where we bring you real stories, strategies and science from the world of functional medicine. I'm Dr Mitchell Rasmussen, a functional medicine practitioner.

Speaker 2:

And I'm Kate Daugherty, a certified nutritionist. We are the owners of the Facility, a functional medicine clinic here in Denver, Colorado.

Speaker 1:

We help people improve their biology and get out of their own way. We help people improve their biology and get out of their own way. In my view, our work is about getting to know the person with the condition much more than it's about understanding which condition the person has. As I always say, diagnose the biology, not the disease.

Speaker 2:

On this podcast. We break down complex health topics, share real patient cases anonymized, of course and explore cutting-edge wellness strategies so you can make informed decisions about your health. Quick heads up before we dive in this podcast is for education and general information only. We're here to share insights, not to diagnose or treat. So if you're dealing with a health issue, chat with a qualified healthcare provider before making any changes. All right, let's get into it. Hello, hello.

Speaker 2:

This week we have a solo episode coming from Dr Mitchell, but I felt like it was relevant for me to jump in quickly before I turn it over to him. Yes, his brain works on another level. No, I don't expect you to understand every single detail he talks about. He's going to talk in detail about the interplay of stress hormones like cortisol and other signaling molecules, and inflammation, and because I know that the best way for learning is repeated exposure to concepts, I will be transforming this episode into a short blog post where you can read through it, see some graphs, maybe get an even better grasp on the stress-cortisol-inflammation relationship. You can find that link in the episode notes or navigate to the blog on our website, thefacilitydenvercom. He'll end the episode saying something that I want to highlight. So let me get my Mitchell voice in.

Speaker 1:

He says I want you Hold on, hold on.

Speaker 2:

Let me just edit this in I also want you to feel like your mind has been expanded a bit. So that's my challenge for you Go into this ready to grow.

Speaker 1:

All right, everybody, it's just me, dr Rasmussen, today, solo episode. I was hoping to sit down and just spend a few minutes talking about a common picture that we see with our client population where people are chronically inflamed despite the fact that on a blood or a salivary cortisol test, their cortisol is through the roof. It's an odd clinical picture on the outset, but there's actually some really common mechanisms that lead to this type of picture Starting out. Why does someone have cortisol? Right? Cortisol is a hormone that's released a few minutes after a stressor. That essentially, is meant to trigger the resolution of inflammation and immune response and stress response so that you can come back down to homeostasis.

Speaker 1:

Any stressor I always say that's real or perceived, so this could be somebody chasing you, this could be an injury or an illness. It could also be psychological based, post-trauma based, anything like that that causes the expression of stress within the brain, leads to the release of something called corticotropin releasing hormone, crh. Crh has a couple different jobs. The first job it does is it raises the sympathetic nervous system through the spinal cord responses, where we get release of adrenaline. That's a very instant response. It's meant to raise our blood pressure, raise our inflammation, essentially raise our acuity of vision, blood flow to our lungs and heart and essentially prime us to get ready to run from a threat. That's that heart racing effect that we feel when stress sets in. That is all well and good to get us surviving in that moment. But then the job is really to have a second cascade of hormone signaling that brings us back down to baseline and that takes a few minutes after the adrenaline release. And that's these, this expression of cortisol release from the adrenal glands, which is really meant to come in, oppose the adrenaline. Let that wear off and then let us come back down to a less inflamed, less survival mode expression of our nervous system. So essentially we have a stressor brain drive signaling. Signaling leads to immune responses and nervous system responses and then ideally, once that threat has left the building, cortisol can come in and bring us back down.

Speaker 1:

But oftentimes that fails. That system is either overburdened because of chronic stress or the system is simply kicking out so much for so long that we become what I call death by a thousand paper cuts, where we have so many different stressors happening coming in to the system that we can never really come back down to homeostasis. And this is a hallmark of this picture we see with the inflammation, despite the copious amounts of this anti-inflammatory compound floating through the bloodstream. When cortisol fails to inhibit inflammation, we get stuck in this loop, and this loop is this body inflammation leading to brain inflammation. The brain inflammation activates the sympathetic nervous system, which actually leads to our macrophages to produce more inflammatory signaling, specifically things like NF-kappa B and TNF-alpha. Those actually drive further body inflammation and then this keeps spinning. And it's spinning because these macrophage-derived proteins are not being effectively inhibited by the cortisol, because we got into this chronic state.

Speaker 1:

And more broadly, I want you to think about this NF-kappa B, how it actually. I called it earlier in a previous episode the kindling of inflammation. This NF-kappa B is a series of gene transcription factors which essentially activates a series of proteins that lead to what's called inflammasome assembly. When we have that activation, we can't promote autophagy or the clearance of dead or dying tissues, and when we can't promote autophagy, we actually get damaged mitochondria. When we have damaged mitochondria, we have poor function of what's called the Krebs cycle, which is how you make energy, and then we have a certain series of metabolites that cannot be produced, and these metabolites are massively important for receptor responses to the cortisol. So this would be a person who has the high cortisol but the body has quit listening. Keep in mind you can become resistant to pretty much any hormone. Insulin resistance is really well known. Leptin resistance is something we see quite often in people who are struggling with their weight. Well, cortisol receptor downregulation or poor resistance is absolutely relevant for a lot of people that we see and it's just so common.

Speaker 1:

I want to take a step back for a second. The frontal cortex is a massive signaling organ. It might be 90% of its job might be to actually signal to the brainstem. And when we have body inflammation leading to brain inflammation, you are not getting good firing of that frontal lobe. And when you have poor firing of the frontal lobe now, you don't get signaling to the brain stem which actually leads to lower vagal motor outflow. And, as we should know by now, the vagus nerve is a profound anti-inflammatory nerve. So if, again, taking our step back, chronic brain inflammation from body inflammation which leads to that high cortisol, that upregulation of corticotropin-releasing hormone leading to this poor frequency of firing of these prefrontal cortex neurons, leads to less activation of the brainstem the brainstem is the house of the vagus nerve. You're going to get less vagal motor outflow and then now you're losing that anti-inflammatory component of the vagus nerve. You're going to get less vagal motor outflow and then now you're losing that anti-inflammatory component of the vagus nerve. This is when we'll start to see motility concerns, bloating, food sensitivities, things of the like all because of the chronic stress. And when you have poor motility you're more likely to allow bacteria to kind of move up into the small bowel, which will trigger intestinal dysbiosis or even things like SIBO small intestinal bacterial overgrowth which again reinforces the body inflammation. And we're back where we started. I tell patients this all the time Anything that causes gut inflammation leads to body inflammation and an inflamed body always, eventually, every single time, will lead to an inflamed brain. The response to inflammation within the brain is a release of more of the stress chemistry and now we've essentially just looped ourself in to this reinforcing response.

Speaker 1:

I mentioned earlier receptor responsiveness. Here is where we see things like vitamin D deficiency, leading to that when we have that low, we get a weird ratio of these receptors to glucocorticoids, to cortisol, and that ratio dysregulation because of low vitamin D is actually associated with poor responsiveness to cortisol. There was a fascinating study in immunology research back in 2021 that showed this mechanism and it's really all about that receptor. We've got the receptor alpha, we've got the receptor beta and then a low alpha to beta ratio we see, when caused by low vitamin D actually leads to this hyporesponsiveness is how they call it to glucocorticoids. So this could be because of low vitamin D or if you have poor kidney conversion, this could be because of low vitamin D or if you have poor kidney conversion or poor conversion outside the kidney. I should say, if that's not robust, you're naturally going to get less cortisol responses. Blood levels of vitamin D are relevant, but this will get into another conversation in the future about how sometimes a blood level has very little to do with how much vitamin D you're taking and it actually is being lowered due to suppression of receptors from things like Epstein-Barr virus, which is something that we inventory in every single patient dealing with fatigue or chronic inflammation is. I'm really curious if there's potentially you had mono 15, 20 years ago and maybe there's some sort of flare of this chronic Epstein-Barr virus or a new infection and things like that. That's something that we look at.

Speaker 1:

A last concept here I think about is poor metabolic integrity. Again, body inflammation leads to brain inflammation, which gets reinforced because brain inflammation causes sympathetic nervous system activation, which leads to more inflammation. That, done chronically, leads to receptor downregulation for cortisol, the anti-inflammatory, which essentially gets us stuck in this inflamed and exhausted state. Here's where poor metabolic integrity is so important. Cortisol can fail to inhibit inflammation when we have poor mitochondrial function. Mitochondria right, the powerhouse of the cell, whatever. Whatever. They're actually responsible not only for making energy but helping trigger when cells need to die. Give me a second. Just had to get a sip of coffee because it's about to get heavy.

Speaker 1:

There was a paper in the journal Nature, actually just this last year. It was pretty illuminating and they showed that when we interfere with the Krebs cycle production of certain metabolites specifically the one they were talking about was itaconate, which is an interesting metabolite from the Krebs cycle when we have that interference due to poor mitochondrial function or poor metabolic integrity, this actually prevents things like cortisol from accomplishing these anti-inflammatory effects. And what they're suggesting is that when you have a poor metabolism due to things like insulin resistance or chronic infections or nutrient deficiencies right, it's all about stress, toxins and deficiencies driving this poor metabolic integrity. We know, when you have metabolic issues and mitochondrial dysfunction. You will not get this anti-inflammatory effect from cortisol when your body's producing it. And then again back to the beginning when this persistence of inflammation continues again leading to this corticotropin-releasing hormone secretion by the hypothalamus. This is going to again drive more cortisol production, but the CRH will continue to drive the nervous system activation which leads to the body inflammation, to the brain inflammation, to the sympathetic nervous system loop, and we've known this for at least 15 years that this essentially leads to an inflamed person with lots of cortisol, but unfortunately the cortisol is not inhibiting their inflammation.

Speaker 1:

So in the big picture, here's what I think about with all this information, thinking about the relationship here we need to find for each individual person what are the biggest sources of inflammation. Is it the food you're eating? Is it too much exercise or maybe not enough exercise, poor sleep, high, chronic, unmitigatable stress, chronic infections, etc. Those are the places that we must start first. What I always say is I want to pull back the most obvious threats and typically that's going to be the food we put in our mouth. The food you put in your mouth will create inflammation every time as a normal oral tolerogenic mechanism by your body. But we don't want to be eating foods that cause excessive inflammation or leaky gut, and for people that's different. You know, specifically for me I struggle with dairy. It triggers eczema. It doesn't cause any sort of gut issues, so so I tend to not 100% pull that out because I enjoy ice cream and pastries and things like that. But I know that a certain amount of that, too many days in a row, will lead to a flare of eczema and I know, I know if I'm waiting for it to break down on the outside, it's clearly doing something on the inside. But hey, I'm a person, I enjoy things like that sometimes and you know, I guess I'm a stubborn old dog. So what can you do? So first we're going to inventory this person to see where I can pull back obvious sources of inflammation, and then I really want to think about how can I support these mitochondria performing this autophagy. How can I support these mitochondria performing this autophagy so that I can downregulate that activation of NF-kappa B in the inflammasome? When I think about autophagy, I need adequate vitamin D and I actually also need adequate what's called Th1 cells, things like natural killer cells and CD8 and all sorts of other cells that can essentially help me produce a compound called interferon gamma and that will help support this autophagy process.

Speaker 1:

When I think about the central nervous system, it depends on where you're at. Do you have an iron deficiency? Do you have a B vitamin deficiency? Do you smoke? Do you have poor blood sugar regulation? And what I'm getting at. What do neurons need? Neurons need oxygen, they need stimulation and they need fuel. So if your nervous system is chronically activated because of stress and you have hypoxia because you live in Colorado and you have an iron deficiency because you are on a proton pump inhibitor because of your heartburn again we could keep going around and around and around. Now you have two drivers of hypoxia. Hypoxia is an independent driver of inflammation through a compound called HIF-1-alpha. So if I know my nervous system needs oxygen, stimulation and fuel and I'm living at altitude and I have a nutrient known to help carry oxygen, like iron, which is deficient, that's going to become an independent driver of body inflammation, which again leads to brain inflammation and which drives the production of corticotropin-releasing hormone within the central nervous system.

Speaker 1:

And there I'm looped again. Let's say insulin resistance. Same thing. My brain will become really affected by insulin resistance and now I've lost my prime fuel source for the brain and again, if my frontal cortex is not getting adequate fuel it can't signal the brainstem, which is again 90% of its job. If I can't signal the brainstem, I can't activate the vagus nerve motor component robustly enough and that will again yield and turn around more inflammation, because the vagus nerve is an anti-inflammatory nerve. So CNS circulatory support, neurotransmitter support, cns repair support If there was some type of injury. That's a vital aspect of attention for us as well to help mitigate some of that chronic CRH production by the hypothalamus. And then histamine. We know that histamine affects cells all over the body and especially within the central nervous system. If I'm eating certain foods that cause a histamine release chronically, that will absolutely lead to issues within the central nervous system.

Speaker 1:

A big, huge thing that I've already mentioned a couple times is that vagus nerve. Do we need to do vagal nerve activation with some sort of neck-based device or a transcutaneous vagal nerve stimulation through the auricular pathway on the left ear? Is that a way to get into this? Should we do a coffee enema, which we know can have vagal outflow activities? What about things like humming or gargling? Those are all great.

Speaker 1:

The first one I always tell you is chew your food. Chewing your food, that's called mastication. Mastication activates the brainstem which drives profound engagement with the vagus nerve, and then the vagus nerve can turn around and help you make stomach acid drive, pancreatic enzyme release, pull blood into our intestines so that we have adequate motility, so that we can keep things moving, so that we don't get SIBO and, as we said earlier, sibo leads to inflammation. So I think you're getting this picture that oftentimes we find ourselves stuck. There's so many factors that lead to these reinforcing loops and I really view our job as one where we need to get in and pull back as many factors as possible and oftentimes, again, for this broader picture, pull out obvious drivers of stress or of inflammation in the system and then let's get into vagal nerve activation, a typical first patient you'll hear. Avoid liquids at mealtimes, don't eat while distracted, chew your food and let's do some humming and gargling. I want you to pull out gluten, dairy and soy, because we're not going to waste your money running a piece of crap food sensitivity test. We know that they don't really tell us much relevant information, in my opinion. So we'll just pull out some obvious sources and let's work on balancing the circadian rhythm to get you to sleep at night. That oftentimes really gets us rolling in the right direction.

Speaker 1:

While we're waiting for initial blood work to come back, are we testing you for mold or Lyme disease? What deficiencies do we have? Things like that. Those will at least those few initial changes will get us started while we're waiting for the information to come in to support the real, precise clinical interventions that will be next. I want to leave it there. There's a lot more I can say absolutely, and I think we'll talk about this again in the future. There's a lot more I can say absolutely, and I think we'll talk about this again in the future. I just wanted to get a little bit of information out on what we see happening so often with our patients who are stuck in this inflamed and stressed picture. I want you to feel hopeful that there's things that you can do struggling with a thing like this, and I also want you to feel like your mind has been expanded a bit to start to think about how all of these pieces relate together. Thank you for listening.

Speaker 2:

And that's a wrap for this episode of Facilitated. If you enjoyed it, hit subscribe because, let's be honest, you'll forget otherwise. And if you really loved it, please leave us a review. Not only does it make Mitchell feel warm and fuzzy inside, but it also helps more people find functional medicine without falling into a Google rabbit hole. For more about what we do at the facility, check out our website, wwwthefacilitydenvercom. You can also follow us on Instagram, at thefacilitydenver, for extra tips behind the scenes, fun and updates on new episodes. Thanks for listening. Now go facilitate your own health and we'll see you next time.