Stress, Inflammation, and the Functional Medicine Model

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The inflammatory pathway is pivotal in the pathogenesis of many chronic diseases.1,2 In fact, 75% to 90% of human disease is related to stress and inflammation, including most cardiovascular and metabolic diseases and neurodegenerative disorders.1 Studies suggest that chronic stress results in glucocorticoid receptor resistance that, in turn, results in failure to downregulate inflammatory responses.3-5

In this video, IFM educator Patrick Hanaway, MD, describes the role of stress and inflammation in cardiovascular and cardiometabolic health:

(Video Time: 2 minutes) Patrick Hanaway, MD, is a board-certified family physician who teaches on the clinical application of nutritional biochemistry, with an emphasis on digestion, immunology, mitochondrial function, and wellness. Dr. Hanaway is the former medical director of the Center for Functional Medicine at the Cleveland Clinic.

Large bodies of research indicate that chronic stress, whether experienced in early life or as an adult, is linked to increased coronary heart disease risk.1,6-7 In particular, childhood adversity, including physical and sexual abuse in childhood, has been shown to relate to higher morbidity of cardiovascular events.8,9 Work-related stressors, poor sleep, and emotional disturbances have been correlated with adult-related cardiovascular disease.1 Racism and discrimination create additional daily stressors for Black, Indigenous, and People of Color (BIPOC) communities, impacting their increased cardiovascular disease risks.10-13

A 2018 finding using data from the Jackson Heart Study suggested that in African American adults, global stress (overall stress level) and major life events were associated with increased risk of metabolic syndrome (MetS) severity.14 Additionally, men and women’s MetS and stress responses varied in severity. For example, men significantly increased their MetS severity at medium levels of stress, whereas women significantly increased their MetS severity at high levels of stress.14

Chronic psychological stress and inflammation are also associated with a greater risk of depression, autoimmune diseases, upper respiratory infections, and poor wound healing.3 In a large study published in 2019 in the journal Molecular Psychiatry, a team of researchers from Cambridge examined the link between depression and coronary heart disease.15 Their findings suggest that the connection between these two conditions cannot be explained by a common genetic predisposition; rather, it is environmentally related. They used Mendelian randomization to investigate 15 biomarkers associated with the risk of coronary heart disease; of these biomarkers, they found that triglycerides and the inflammation-related proteins IL-6 and CRP were also risk factors for depression. What’s more, the authors note that with regard to shared environmental factors, the depression–coronary heart disease comorbidity could be linked with early-life factors influencing inflammatory regulation, such as impaired fetal development or childhood maltreatment/trauma. Low birth weight and childhood maltreatment were associated with increased levels of circulating inflammatory markers, depression, and coronary heart disease in adulthood.15

Similarly, researchers have for years speculated that disorders of the gastrointestinal tract, such as Crohn’s disease and ulcerative colitis, are related to stress and inflammation,16 but the underlying mechanism remained largely unresolved. An elegant 2018 study in mice suggests a clue, showing that chronic stress disturbs gut microbiota, triggering an immune system response and facilitating dextran sulfate sodium–induced colitis.17 Recently, a 2020 systematic review of 19 clinical prospective cohort studies also concluded that while evidence suggests that psychological factors have a weak to moderate causal involvement in inflammatory bowel disease symptom exacerbation, overall results remain inconclusive and additional studies are warranted.18

Stress Management Interventions

With a wide range of stress-related chronic diseases on the rise, how can functional medicine clinicians target stress-related factors with interventions that improve the health of their patients? Accumulating evidence points to the beneficial effects of regular exercise in preventing or improving the metabolic and psychological comorbidities brought about by chronic stress.19 Recent meta-analyses indicate that physical exercise improves the inflammatory state in children with obesity20 and improves inflammatory biomarkers in middle-aged and older adults.21

A first-of-its-kind study on yoga and meditation showed improvement in biomarkers of cellular aging, which are associated with oxidative stress and complex lifestyle diseases like depression, diabetes, and cardiovascular disease.22 The researchers suggested that the improvement in stress and inflammatory response was mediated by changes in cortisol, β-endorphin, IL-6, and other factors, with regulation by changes in the brain through the hypothalamic-pituitary-adrenal (HPA) axis.22

More recently, a 2023 systematic review of 21 studies suggests that a single session of yoga (or components of yoga like meditation and breathing techniques) may be effective in reducing acute stress reactivity in adults.23 The study measured both physiological outcomes like heart rate and blood pressure as well as psychological outcomes like anxiety. Nine out of 12 (75%) studies having 15-20 min meditation practice reported significant effect on stress reactivity in at least one outcome measure, and six out of nine (67%) studies with <12 min practice duration reported favorable outcomes in one of the outcome measures. Outcome measures most consistently attenuated by yoga-based practices were heart rate variability, skin conductance, and cortisol.23

Many diseases stemming from chronic stress and inflammation have early warning signs, meaning some cases may be prevented or improved with lifestyle changes that help manage stress. The functional medicine model focuses in on identifying stress as a cause of dysfunction and utilizing specific interventions like exercise, meditation, and yoga that work for the individual patient.

The IFM Toolkit provides easy and accessible resources to personalize lifestyle-based therapies and includes Strategies for Transforming Stress. This toolkit item suggests a range of stress-relief practices, from community support, spiritual practice, and laughter to journaling, practicing gratitude, and meditation. Other tools such as the functional medicine timeline can also help clinicians identify areas of life where stress may be problematic and design treatments that focus on improving stress management. Learn more about tools and strategies to help patients achieve sustainable lifestyle change and improve their well-being through IFM’s new course Lifestyle: The Foundations of Functional Medicine.

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