How Do Stress & Inflammation Contribute to Chronic Disease?

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The relationship between stress and inflammation has been studied rigorously, with researchers continuing to find evidence that 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 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.

The Impact of Stress

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 In particular, childhood adversity, including physical and sexual abuse in childhood, has been shown to relate to higher morbidity of cardiovascular events.7,8 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.9-12

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.13 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.13

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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.14 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.14

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,15 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.16 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.17

Managing Stress

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.18 Recent meta-analyses indicate that physical exercise improves the inflammatory state in children with obesity19 and improves inflammatory biomarkers in middle-aged and older adults.20

In 2017, 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.21 The researchers suggested that the improvement in stress and inflammatory response was mediated by changes in cortisol, ?-endorphin, IL-6, and other factors, with regulation by changes in the brain through the hypothalamic-pituitary-adrenal (HPA) axis.21

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. 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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  1. Liu YZ, Wang YX, Jiang CL. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci. 2017;11:316. doi:10.3389/fnhum.2017.00316
  2. Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822-1832. doi:10.1038/s41591-019-0675-0
  3. Cohen S, Janicki-Deverts D, Doyle WJ, et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci U S A. 2012;109(16):5995-5999. doi:10.1073/pnas.1118355109
  4. Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol. 2002;21(6):531-541. doi:10.1037//0278-6133.21.6.531
  5. Walsh CP, Bovbjerg DH, Marsland AL. Glucocorticoid resistance and ?2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: a systematic review across species. Neurosci Biobehav Rev. 2021;128:117-135. doi:10.1016/j.neubiorev.2021.06.013
  6. Su S, Jimenez MP, Roberts CTF, Loucks EB. The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms. Curr Cardiol Rep. 2015;17(10):88. doi:10.1007/s11886-015-0645-1
  7. Rich-Edwards JW, Mason S, Rexrode K, et al. Physical and sexual abuse in childhood as predictors of early-onset cardiovascular events in women. Circulation. 2012;126(8):920-927. doi:10.1161/CIRCULATIONAHA.111.076877
  8. Kreatsoulas C, Fleegler EW, Kubzansky LD, McGorrian CM, Subramanian SV. Young adults and adverse childhood events: a potent measure of cardiovascular risk. Am J Med. 2019;132(5):605-613. doi:10.1016/j.amjmed.2018.12.022
  9. Acosta JN, Leasure AC, Both CP, et al. Cardiovascular health disparities in racial and other underrepresented groups: initial results from the All of Us research program. J Am Heart Assoc. 2021;10(17):e021724. doi:10.1161/JAHA.121.021724
  10. Javed Z, Maqsood MH, Amin Z, Nasir K. Race and ethnicity and cardiometabolic risk profile: disparities across income and health insurance in a national sample of US adults. J Public Health Manag Pract. 2022;28(Suppl 1):S91-S100. doi:10.1097/PHH.0000000000001441
  11.  Javed Z, Haisum Maqsood M, Yahya T, et al. Race, racism, and cardiovascular health: applying a social determinants of health framework to racial/ethnic disparities in cardiovascular disease. Circ Cardiovasc Qual Outcomes. 2022;15(1):e007917. doi:10.1161/CIRCOUTCOMES.121.007917
  12.  Panza GA, Puhl RM, Taylor BA, Zaleski AL, Livingston J, Pescatello LS. Links between discrimination and cardiovascular health among socially stigmatized groups: a systematic review. PLoS One. 2019;14(6):e0217623. doi:10.1371/journal.pone.0217623
  13.  Cardel MI, Min YI, Sims M, et al. Association of psychosocial stressors with metabolic syndrome severity among African Americans in the Jackson Heart Study. Psychoneuroendocrinology. 2018;90:141-147. doi:10.1016/j.psyneuen.2018.02.014
  14.  Khandaker GM, Zuber V, Rees JMB, et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Mol Psychiatry. 2020;25(7):1477-1486. doi:10.1038/s41380-019-0395-3
  15.  Pereira C, Grácio D, Teixeira JP, Magro F. Oxidative stress and DNA damage: implications in inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(10):2403-2417. doi:10.1097/MIB.0000000000000506
  16.  Gao X, Cao Q, Cheng Y, et al. Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response. Proc Natl Acad Sci U S A. 2018;115(13):E2960-E2969. doi:10.1073/pnas.1720696115
  17.  Schoultz M, Beattie M, Gorely T, Leung J. Assessment of causal link between psychological factors and symptom exacerbation in inflammatory bowel disease: a systematic review utilising Bradford Hill criteria and meta-analysis of prospective cohort studies. Syst Rev. 2020;9(1):169. doi:10.1186/s13643-020-01426-2
  18.  Tsatsoulis A, Fountoulakis S. The protective role of exercise on stress system dysregulation and comorbidities. Ann N Y Acad Sci. 2006;1083:196-213. doi:10.1196/annals.1367.020
  19.  Sirico F, Bianco A, D’Alicandro G, et al. Effects of physical exercise on adiponectin, leptin, and inflammatory markers in childhood obesity: systematic review and meta-analysis. Child Obes. 2018;14(4):207-217. doi:10.1089/chi.2017.0269
  20.  Zheng G, Qiu P, Xia R, et al. Effect of aerobic exercise on inflammatory markers in healthy middle-aged and older adults: a systematic review and meta-analysis of randomized controlled trials. Front Aging Neurosci. 2019;11:98. doi:10.3389/fnagi.2019.00098
  21.  Tolahunase M, Sagar R, Dada R. Impact of yoga and meditation on cellular aging in apparently healthy individuals: a prospective, open-label single-arm exploratory study. Oxid Med Cell Longev. 2017;2017:7928981. doi:10.1155/2017/7928981


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