How Do Stress & Inflammation Contribute to Chronic Disease?

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.

In fact, 75% to 90% of human disease is related to stress and inflammation, including cardiovascular and metabolic diseases and neurodegenerative disorders. Studies suggest that chronic stress results in glucocorticoid receptor resistance that, in turn, results in failure to down regulate inflammatory responses.

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. Work-related stressors, poor sleep, and emotional disturbances have been correlated with adult-related cardiovascular disease.

Chronic psychological stress and inflammation are also associated with a greater risk of depression, autoimmune diseases, upper respiratory infections, and poor wound healing. 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. 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 randomisation 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. 

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, 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. 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.

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. Recent meta-analyses indicate that physical exercise improves inflammatory biomarkers in middle-aged and older adults.

In 2017, a first-of-its-kind study on yoga and meditation showed improvement in biomarkers of cellular ageing, which are associated with oxidative stress and complex lifestyle diseases like depression, diabetes, and cardiovascular disease. The researchers suggested that the improvement in stress and inflammatory response was mediated by changes in cortisol,  IL-6, and other factors, with regulation by changes in the brain through the hypothalamic-pituitary-adrenal (HPA) axis.

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. 

Two most commonly used lab measurements for inflammation.

SED RATE (ESR): The erythrocyte sedimentation rate (ESR) determination is one of the first inflammatory markers discovered and utilised clinically. 

CRP (HS): C-reactive protein (CRP) is produced by the liver in response to stress and inflammation as signalled by the brain to the HPA axis via interleukin 6.  CRP was discovered in 1930 by isolating it from the blood of patients with a particular type of pneumonia. Later research, and the development of a more sensitive version of the test (hs-CRP), showed that CRP-levels could be measured in blood in response to inflammation.

References
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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
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
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
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