Linking Stress and Inflammation to Chronic Disease

Kalea Wattles, ND, IFMCP
Are you feeling stressed today? Researchers estimate that 55% of all Americans feel stressed during the day. And while acute stress is a normal part of the human experience, prolonged exposure to chronic psychological and physiological stressors may accelerate some disease processes. The experiences that shape the stress response may also influence sleep patterns, food intake, blood sugar imbalances, and cardiovascular function, leading to chronic illness. The good news is that many diseases stemming from chronic stress and inflammation have early warning signs, meaning some cases can be prevented or improved with lifestyle changes that help to manage stress.

On this episode of Pathways to Well-Being, we welcome Dr. Mylène Huynh to explore the connection between stress, inflammation, and disease, highlighting ways to effectively transform stress and improve health. Welcome to the show, Dr. Huynh!

Mylène Huynh, MD, MPH, IFMCP
Thank you for having me here today. I am looking forward to discussing this very important topic since chronic stress can impact all aspects of our health.

Kalea Wattles
Well, something I love about functional medicine is we recognize and we honor this mind-body connection. So I'm really looking forward to hearing your perspective and your clinical experience. And we know that psychological stress is not only this mental-emotional experience of adversity, but it can also have really significant physiological influences. And to get our conversation started today, I was hoping you would tell us a little bit about the physiology of stress, how stress shows up in our physical body.

Mylène Huynh
Right, well, I think before we talk about the physiology of stress, I think it's important to maybe distinguish between distress, chronic stress, and eustress.

Kalea Wattles
Yeah.

Mylène Huynh
Yeah, I think of distress as an experience of feeling overwhelmed; often can be triggered by an acute event in which we sense danger or fear such as being in a motor vehicle accident or facing death of a loved one. Distress often immediately activate the sympathetic nervous system and/or fight-and-flight response can react, and then prolonged state of distress or chronic stress can disrupt our entire physiological and biological system and can result in both physical and mental health challenges. 

Eustress, some people talk about eustress, on the other hand, can be considered as a positive stress. We think of eustress as short-term stress without the sense of danger, of course. And with the challenges that we can handle, eustress can often motivate us to take action and even improve our performance. For example, eustress can help us prepare for an exam, help motivate us to prepare harder, focus, and perform better. So, when it comes to stress, the physiologic changes in stress, duration is the factor. Short-term stress appear to have no physiological harm and can even enhance our performance. Whereas chronic psychological stress can negatively impact on entire physiological and biological system and, as you stated, can lead to various health challenges, from cardiovascular diseases to autoimmune, gastrointestinal, and metabolic disorder, as well as the anxiety and depression.

Kalea Wattles
It's very interesting to think about really the dose. The dose of the duration of the stressor influencing how it shows up in our health. And really, what my takeaway from what you're saying is there are situations in which stress can actually be beneficial for our body.

Mylène Huynh
That's right, short doses, bursts of stress, especially when there's no fear or danger associated, help us perform better, and we have to come down, though, when we have stress, our sympathetic nervous system get activated. But the key is to come back down to the parasympathetic system being dominant as a way to relax and allow the body to heal.

Kalea Wattles
Well, as we're exploring all the different ways that stress can impact our physiology, will you help us link stress and connect it to inflammation, chronic inflammation in particular?

Mylène Huynh
All right, stress-related inflammation can impact several physiological and biological systems in unison, at the same time, and can cause whole-body inflammation and dysregulation. And if you want to compare that to like the onset of systemic inflammation, other causes usually, that starts at one origin like an infection or physical injury and progress to other system. And because chronic stress is subjective, stress is subjective and unseen, the impact of stress-related inflammation could go undetected clinically for months or years. 

Stress-related inflammation can disrupt, I think of five major system in the body. That autonomic nervous system: chronic stress disrupt the balance between the sympathetic fight or flight and parasympathetic, which is all rest and digest, and chronic stress autonomic nervous system can remain in flight-or-fight mode and the cortisol remain chronically elevated. The activated autonomic nervous system plays a role in immune function and can promote a pro-inflammatory response. The receptors on immune cell can become desensitized to chronically elevated stress hormone that leads to immune dysregulation and several autoimmune disorders. Chronic stress can also cause persistent activation of the HPA axis, resulting in chronically elevated level of stress hormone such as cortisol, epinephrine, which can lead to metabolic and mood disorders. And the cardiovascular system is also impacted by the chronic stress via the vagus nerve. And our patient may experience tachycardia, elevated blood pressure, and possibly disruption of the heart electrical system. Chronic stress can also impact the gut-brain axis, causing altered microbiome and intestinal permeability. So, stress-related inflammation appears to negatively impact the entire psycho-endo-neuro-immunology of our system.

Kalea Wattles
Just listening to you talk, I'm visualizing the functional medicine matrix and all of these connecting points, we just, from your description, I heard the assimilation note of the matrix, we had defense and repair, energy, communication, transport. I mean, I'm really seeing the matrix light up here and thinking of these foundational tools, the functional medicine matrix and the timeline. You mentioned how the duration of exposure to a stressor really determines how it affects someone's health. How do you track or even find the initiator of a big stressor on someone's timeline? How are you incorporating that into the work that you do with patients?

Mylène Huynh
That's a great question. You mentioned the matrix, and you're absolutely right. The stress-related inflammation impact all the nodes on the matrix. If you examine it quickly, I love the matrix, so we're going to walk through it, if that's okay.

Kalea Wattles
Yes, please.

Mylène Huynh
Assimilation, digestion due to impact on the gut-brain axis, it caused altered microbiome, intestinal permeability. So patient who experience chronic stress may show up complaining of GI bloating, poor digestion, poor appetite. 

In terms of defense and repair, chronic stress can dysregulate the immune system, increasing expression of pro-inflammatory cytokines like IL-1, IL-6, and tumor necrosis factor and C-reactive protein. Chronic stress has also been shown to decrease natural killer cell function, which is our first line of immune defense. So patient may present with frequent upper respiratory infection, perhaps shingles or other autoimmune conditions. 

In terms of energy, chronic stress has been shown to decrease mitochondrial energy production. It decreases ATP synthesis. So patient may present with fatigue, excessive fatigue. 

In terms of biotransformation and elimination, chronic stress can decrease glutathione in our tissue and impact metabolism. I was fascinated to read that there are studies that show that chronic stress can upregulate our CYP enzyme that metabolize the majority of all prescribed drugs, which can result in increased metabolism and, consequently, ineffective pharmacotherapy. So when patient is under a lot of stress and we prescribe medication, it may not be effective. 

Transport. Transport includes cardiovascular and lymphatic system. We already talk about chronic stress impact on the cardiovascular system in terms of blood pressure, heart rate, electrical conduction system. It also leads to risk of vascular atherosclerosis and risk of myocardial infarction and stroke, and persistent high cortisol associated with chronic stress can impede lymphatic flow and decreasing our ability to remove toxin and waste from our body. 

In terms of communication, dysregulation of the HPA axis due to chronic stress lead to metabolic disorder, contributing to obesity as well as mental health issues such as depression and anxiety. 

And lastly, structural integrity. Chronic stress increases the production of reactive oxygen species, leading to oxidative stress that could lead to cellular dysfunction, DNA damage, even altered gene expression, and prolonged activation of the stress response systems tend to create what we call allostatic load on the body that result in wear and tear on our system. And because chronic stress often create muscle tension, our patient often present with neck and back pain, tension headaches, migraines, and muscle spasm associated with lactic acid buildup. So it really touch on all of the matrix nodes.

Kalea Wattles
I mean, I think that is, really underscores why we have the mental-emotional-spiritual component right at the center of the matrix, right? Because it really is touching every single one of those nodes.

Mylène Huynh
Absolutely. The mental, emotional, spiritual aspect is something that we should address with all our patient because it is the center, and our mind really control the physiology and the biology of how a body responds to stress.

Kalea Wattles
So now that we're visualizing that matrix, how do we bring in the timeline as we're working, as we're working with patients or looking at our own timeline and identifying how stressors have shaped our health trajectory?

Mylène Huynh
Yeah, I think in terms of the timeline, chronic stress can be an antecedent, could be past traumatic events, adverse childhood events, or stress that have not been resolved in terms of post-traumatic stress disorder. Paying attention to changes in patient clinical presentation, their glucose could be elevated, and cholesterol could change based on just stress without changing anything else in terms of their behavior. Also, paying attention to their lifestyle behavior in terms of sleep, exercise routine, their dietary habits, so stress is a touch point that affects the, could be part of the antecedents, certainly a trigger, and part of our mediators.

Kalea Wattles
Indeed, you just reminded me, something I think about quite often is how stress impacts our ability to meaningfully engage in many of the other modifiable lifestyle factors, right? When we're so stressed out, it's hard to eat healthy and to make time for exercise and to nourish our relationships. I wanted to get your perspective on how some of our social determinants of health play into this picture of stress and inflammation and how our body is managing these processes.

Mylène Huynh
Yeah, I'm so glad you asked that question because research study have shown that social determinant of health do play a significant role in shaping our stress response and our overall health outcomes. These social determinants may include socioeconomic status, living condition, food and financial security, and potential discrimination. Studies have shown that those with lower income and education level may be exposed to more life stressors, and those living in unsafe or disadvantaged neighborhoods often experience persistent stress. Of course, struggling to meet basic needs is a major source of chronic stress, as well as perceived discrimination based on gender, race, ethnicity, or sexual orientation could be a serious constant stressor. Research study also show that those who face these social determinants of health may have less resources to cope with stress. I think it's something that we all need to be mindful of when caring for our patients. And I wonder in these settings, whether like share medical appointments or group visit would be beneficial to provide the support, to provide the support of shared experiences and perhaps to maximize the use of available resources.

Kalea Wattles
If community is medicine, right, in these situations?

Mylène Huynh
Yeah, loving, supportive communities is truly medicine.

Kalea Wattles
It makes sense to me that we need to consider these factors when we're working with patients who maybe they have chronic systemic inflammation. We've been trying to get to the root of it and considering all these stressors, and it sounds to me from this conversation like there might be a bidirectional communication between stress and inflammation where we're more stressed, we're more inflamed, and then that inflammation is another physiological stressor that makes our body less resilient. Would you say that's true, that there's this bidirectional communication between stress and inflammation?

Mylène Huynh
Absolutely. There's indeed a bidirectional relationship between stress and inflammation. Stress and inflammation have a complex interplay relationship. Chronic stress create a physiological and biological shift toward a pro-inflammatory state in the body. And with a persistent activation of sympathetic and cardiovascular sympathetic system that affects the cardiovascular system and dysregulation of immune system impacting the HPA gut-brain axis. Inflammation can also contribute to increased stress via the HPA axis, which in turn can impact the body stress response system. Inflammation itself can cause imbalances of neurotransmitters such as serotonin and dopamine, which can directly impact our emotional well-being and stress regulation. Also, inflammatory cytokines can cross the blood-brain barrier and activate microglia or brain's immune cells, leading to neuroinflammation. So there is a vicious stress-inflammation bidirectional cycle. Chronic stress leads to inflammation, inflammation impacts brain function and mood, which then increases our susceptibility to stress. So in clinical practice, I think understanding this bidirectional relationship of stress and inflammation is important so that we can assist our patient with strategies that address both stress reduction and inflammation management at the same time.

Kalea Wattles
Right, yes. We'll make sure we talk a little bit more about that, but I want to know how this shows up in your patient population. You've mentioned depression and anxiety, and I think maybe that's intuitive for many of us that if there's stress, there's inflammation, we might see anxiety or depression. What are some of the other common conditions or personas that show up in your patient population where you can identify that this condition really seems to be related to a dysfunctional stress response?

Mylène Huynh
In my practice, I often see digestive issues such as irritable bowel syndrome, heartburn, restless sleep, you mentioned mood changes, weight gain, increased waist-to-hip ratio, and development of metabolic syndrome associated with chronic stress. I sometime also see high cortisol state, increased cholesterol, increased sugar issue with pre-diabetes associated with stress.

Kalea Wattles
Yeah, of course, in the functional medicine world, I have to dive into the gut health aspect here a little bit. That's our favorite thing to talk about. And you've mentioned a few times the gut-brain axis. How are you seeing stress affecting that gut-brain axis? Or maybe even if we zone in on intestinal permeability, how could this maybe predispose us to things like autoimmunity?

Mylène Huynh
Yeah, great question. So the gut-brain axis has a bidirectional communication network between the central nervous system and our GI tract. So stress can induce changes in the composition and diversity of our gut microbiota. And these alteration in our microbiome then can influence stress response and behavior such as leading to mood changes, restless sleep, carb and sugar craving. Stress has also been linked to increase intestinal permeability, as you mentioned, allowing bacterial products such as lipopolysaccharide, a molecule found outer membrane of gram-negative bacteria to enter the bloodstream. That, in turn, trigger the immune responses and systemic inflammation. Chronic stress activate the immune system and can alter the balance toward a pro-inflammatory and inflammatory cytokine state.

Kalea Wattles
There's so many connections here within the intestinal permeability and the way that it can activate our immune system and this chronic inflammation that is just perpetuated. I have almost an entirely fertility-related practice. Is this something you see come up in your practice as well, that those with chronic stress, chronic inflammation are also struggling with fertility issues?

Mylène Huynh
Absolutely, yes. Chronic stress does interfere with reproductive, the reproductive system through the release of excess hormones such as cortisol and epinephrine, which can disrupt ovulation, shorten the luteal face, impact the endometrial lining, and cause menstrual irregularity. In men, chronic stress can cause low testosterone, leading to erectile dysfunction and premature ejaculation. Also, when we're under stress, we have less desire for intimacy, and so we see decreased libido as well. So certainly, chronic stress is a huge factor in fertility.

Kalea Wattles
I think a theme that is coming up for me with all of these conditions is perhaps we need a little support for our nervous system. And so many of us now are talking about heart rate variability, and we know that autonomic dysfunction and heart rate variability are noted in several conditions like PTSD, and in these conditions, there might be an exacerbation of the stress response. Can you talk to us a little bit about the impact of stress on the nervous system and how that might actually affect a patient's experience of stress?

Mylène Huynh
Yeah, I think when we discuss that, let's talk about what happened in our brain or our body when we encounter a stressor. So when we experience a stress, the amygdala gets activated. The amygdala is part of our limbic system that is responsible for emotional processing. It perceives a threat, and it sends a distress signal to the hypothalamus. The hypothalamus, in turn, activates the sympathetic nervous system and then triggers the body fight-or-flight response. At the same time, the adrenal glands may release epinephrine and norepinephrine, causing a cascade of physiological changes that includes heart rate, blood pressure, rapid shallow breathing, heightened alertness, or being on guard. We often see that in PTSD. This cascade event is triggered by both a stressful thought as well as a stressful event. I'll say that again: the cascade of events that how our body reacts to stress is triggered by both a thought as well as a actual event. So the amygdala processes the threat the same way, whether it's a thought, a stressful thought, reliving a stressful experience—we see that often in patients with PTSD—or a current real threat, the amygdala send the same distress signal to the hypothalamus, and the cascade of physiologic changes occur. 

So with that, inflammation can disrupt communication along the stress response pathway through production of pro-inflammatory cytokines, which can further activate the HPA axis and perpetuate our stress response. Inflammation can also affect production and function of neurotransmitters, disrupting normal stress regulation and decreasing our resilience to stress. So in essence, chronic stress shifts the balance of an autonomic nervous system toward persistent and increased sympathetic system activity or fight-or-flight response and directly impacts the vagus nerve, leading to tachycardia, hypertension, reduced heart rate variability, and impaired digestion, mood, and stress responses. And if we are thinking about those stress events after the event happen, that cascade continue.

Kalea Wattles
Hmm, it's so interesting hearing you say it's the event that's happening, but then also the thoughts we have about that event. And I just had a patient tell me yesterday, I think my nervous system can't tell if I'm being chased by a lion or I have an email. And that's such a prime example in action of what you're saying.

Mylène Huynh
Exactly, so our thoughts control a lot of physiology. So in terms of managing chronic stress, it's coming back to being aware of our thoughts and shifting our thoughts toward something that is health-supporting or at least to neutral rather than reliving the thoughts of that negative experience.

Kalea Wattles
Well, let's talk some more about what we're actually going to do about this because we always want to start with those modifiable lifestyle factors. So what are the top lifestyle factors that you're thinking about addressing right away in anyone who has chronic stress?

Mylène Huynh
I think anyone who has chronic stress, I like to look at the five, our five modifiable personal lifestyle. I always start with sleep and nutrition, food, because we all sleep and we all eat, so we start there, right? Adequate, restful sleep and relaxation and maintaining a healthy, balanced diet that include a lot of phytonutrients so that those phytonutrients, phytochemicals are anti-inflammatory, and it help us be more resilient during stress. I always talk about maybe a anti-inflammatory diet focused on vegetable, fruits for phytonutrients as well as whole grains and bean proteins, limiting caffeine and alcohol. I often mention anti-inflammatory properties of certain food and spices that also have adaptogen properties that we can add to our diet during stressful time. Those could include curcumin, ginger, ginseng, cordyceps or reishi mushroom, maca powder, and goji berries. I love maca powder with goji berries, have those in my oatmeal every morning.

Kalea Wattles
Right, so we are getting restful sleep, we're focusing on nutrient density. How about mind-body practices or interventions like yoga? Is this coming up in your treatment plan?

Mylène Huynh

Oh, yes, absolutely. I often emphasize the stress management routine. I love the work of Dr. Herbert Benson, The Relaxation Response that has been shown to decrease back pain and blood pressure and other chronic condition. Also, mindfulness-based stress reduction introduced by Dr. Jon Kabat-Zinn. There are randomized control trial that show that mindfulness-based stress reduction, patients who participate in these as mere short as six weeks have perceived less stress, improved energy, improved sleep, and improved mood. Other lifestyle factor include building loving and supporting connections with others and maintaining a exercise routine as a way to be resilient against stress.

Kalea Wattles
When it comes to the mindfulness practices, I think so many of us know that these are beneficial, and we want to recommend them to patients. Will you just give us a little bit of insight of how you're actually applying these interventions? Are you having patients watch videos? Are you teaching them in the office how to do mindfulness? Are there books you're recommending? How are you giving them the skills they need to do these exercises?

Mylène Huynh
Yeah, I think one thing I observe with patient, you know how we all do vital signs on a patient include heart rate, blood pressure, respiratory rate. I also watch how my patient breathe. When we are under stress, we tend to breathe from like up here like upper chest but not on entire chest. And we tend to breathe faster. So if I notice that I call my patient attention to that, it's like, "Hmm, maybe we can breathe together." I like to take a moment sometime during a visit so that my patient and I can just breathe together. One benefit of that is I get to relax as well where we take a nice deep breath in, we count to four, and then we have a long exhalation, we count to eight. So then we all can be present for each other. And that's one way I do that. I also teach my patients some skill if they feel stressed is to simply to yawn. Like yawning and sighing has been shown to shift our nervous system toward parasympathetic. So just the fact that we yawn, we can move our body toward a more relaxation state.

Kalea Wattles
Just the suggestion of yawning made me, I had to fight every temptation to yawn.

Mylène Huynh
And it's so contagious, right? I mean in a meeting, if it's very contentious and stressful, maybe just yawn. Everybody will yawn and shift to a parasympathetic.

Kalea Wattles
Yawn and sigh. Well, on that note, Dr. Huynh, how are you managing stress in your own life? We all have our stressors. What type of practices do you have to increase your own resiliency to stress?

Mylène Huynh
Yeah, so I grew up practicing mindfulness meditation. I really work hard to pay attention to my thoughts, my own thoughts, which sometimes makes me laugh because, you know, my imagination can go so many places and really practice being in the moment as much as I can. It's interesting, Kalea. So I spent my early years in Vietnam, and the Vietnamese language does not have a past or future tense. There's no past or future in our verb. Everything is in the present. So that's part of the culture is to be in the present as much as we can. I also prioritize sleep. I get about eight to nine hours sleep every night. I find that when I get a good night's sleep, any stressful event I can handle pretty easily. If I don't sleep well, then it's just more difficult. 

I also maintain a regular exercise routine. I attend a yoga class, a 90-minute yoga meditation class about four to five times a week. And I like to create mindful moments during my workday. Like I use the door handle before I go into a patient exam room or while washing my hands before examining a patient as way to stop, breathe, and deeply remind myself to stay in the present moment. When I'm under a lot of stress, I purposely focus on doing one thing at a time and being as present as much as I can while doing that one thing. And I think that's helped me just focus on what you can do and control that one thing. How do you manage stress, Dr. Wattles?

Kalea Wattles
I echo so many of these things you said and it's, this specific example is funny because I have a whiteboard in my office, and right now, if you were to go look at it, it says, "I give myself permission to do one thing at a time."

Mylène Huynh
Oh.

Kalea Wattles
Just, we all need the reminder. And the other thing I've been working on for myself lately is getting out of this, I guess I'll call it urgency culture and just trying to slow down. So, it seems so simple, but this has helped me so much. I will brush my teeth slower. If I'm vacuuming, I will just do it slower, and I can feel my nervous system calming down when I take away the sense of urgency in the task.

Mylène Huynh
Right, and then just being present with that, right?

Kalea Wattles
Yes.

Mylène Huynh
So, in the Asian culture, when we greet each other, we tend to do like this, right? So it's basically mind and body as one, and I'm present for you. So it's a simple gesture, but to remind us to connect on like whatever you're doing, your mind should be there as well as one.

Kalea Wattles
I deeply appreciate and respect and honor these concepts, but I know that they're so hard to apply if you're not used to it. And when we have our patients, they're chronically stressed, they're go, go, go. They're highly activated. How do we help them understand the importance of these practices without it feeling just like another task on the to-do list that they have to check off and it's a chore?

Mylène Huynh
Yeah, that's right. So you can do this without taking additional time. I often prescribe or write on a prescription pad, like, "Breathe in and out deeply, in for four, out for eight, if you, wherever you are at, at a stop sign or red light, instead of looking at your phone, just sit and breathe. Come back to the present. Come back to the present.” I also remind my patient to pay attention to their thoughts, right, because we talk about how our thoughts influence our physiology. So paying attention to our thoughts so that we can shift our thoughts to one of health-supporting. Apparently, did you know that 95% of our thoughts are the same one we had yesterday? We tend to have the same thoughts over and over unless we take control of our thoughts and shift it toward something that's health-supporting.

Kalea Wattles
I believe it. I believe this statistic that you just shared with us. As we're coming to the close of this episode, for anyone who's listening, especially our functional medicine clinicians that are tuning in for this episode, what do you hope they walk away from after hearing this conversation?

Mylène Huynh
Yeah, it's estimated that chronic stress may be responsible for anywhere from 75 to 90% of all chronic diseases that we see in our practice. So when we practice root-cause medicine, chronic stress is that big elephant in the room that we have to address. We discuss that chronic stress is linked to the cardiovascular system, digestive issues, immune system dysregulation, diabetes, dyslipidemia, depression, anxiety, fertility issue, and more. Chronic stress does affect all the nodes on the functional medicine matrix and has to be addressed. And since stress is subjective, we really don't know what our patients may be going through unless we ask. And regarding the timeline, stress can be part of antecedents, triggering events, as well as mediators. 

In clinical practice, we may want to inquire about adverse childhood experiences or prior stressful events, as well as social determinants of health set up for long-term, longstanding stress. And we may want to pay attention to signs of chronic stress such as elevated heart rate, the way a patient breathes, their lifestyle behavior, sleep, and eating habits. There are also clinical markers, waist-to-hip ratio and lab markers, elevated CRP, glucose, fastening insulin, lipid cortisol, and other hormonal markers. 

And I think as healthcare professional we, ourself, face demanding schedule and often high-stress and emotionally challenging situation ourselves. And I understand in the United States, healthcare professionals, we are facing a high burnout rate. So we need to be sure we take care of ourselves. The steps in practicing function medicine, our GO-TO-IT starts with gather. So making time to gather ourselves with mindfulness practices do benefit us and allow us to be present in order to enhance that therapeutic relationship. And I know one thing that's not easy for us healthcare professional to do is to ask for help, is something that I'm working on as well. We need to practice asking for help when we feel overwhelmed or experience stress. And these skills are not something that we learn through our medical training.

Kalea Wattles
Hmm.

Mylène Huynh
So I want to close what poet and author Maya Angelou so wisely stated, "You alone are enough." And in my waiting room, I actually have a frame sign that say, "You are enough," and we are enough. And thank you so much for listening.

Kalea Wattles:
Beautifully said, thank you so much, Dr. Huynh, for being with us and being present. I think we're all more equipped to care for our patients and ourselves. Beautiful conversation today, thank you so much.

Mylène Huynh
Thank you. Thank you, Dr. Wattles.

Kalea Wattles
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