The connection between anxiety and inflammation

Research findings reveal the root causes of anxiety and inflammation and what it means for DCs treating their patients.

Anxiety is normal. Most people feel anxious from time to time. People with an anxiety disorder feel frequent, intense or persistent anxiety. Generalized anxiety disorder is the result of excessive anxiety about two or more aspects of life (work, social relationships, financial matters, etc.). It is often accompanied by symptoms like increased muscle tension, poor concentration and insomnia. Daily worrying for six months or more may signal generalized anxiety disorder. It affects nearly seven million Americans. Another 15 million Americans have social anxiety disorder, six million have panic disorder and nearly eight million have PTSD.

Can stress and anxiety cause inflammation?

Stress has long been associated with anxiety disorders.^1-5 Stress influences the hypothalamic–pituitary–adrenal axis and autonomic nervous system — ultimately affecting the immune system. Chemical changes brought on by chronic stress can lead to inflammation. Stress triggers the release of cortisol, which, under normal conditions, binds to the glucocorticoid receptor and is anti-inflammatory. It decreases lymphocyte proliferation and decreases pro-inflammatory cytokines;⁶ however, chronic stress is another story.

During chronic stress, there is hypersecretion of cortisol, creating a down-regulation of the glucocorticoid receptors. This hinders cortisol binding.⁷ This increases binding to the mineral corticoid receptors, having a pro-inflammatory effect.⁸ The increase in inflammatory by-products further damages the glucocorticoid receptors.⁹ Because of that damage, the normal feedback mechanism is affected. This makes the pituitary think there is not enough cortisol. This ultimately leads to an increase in activity in the sympathetic nervous system.¹⁰ This dysfunction of the hypothalamic–pituitary–adrenal axis is linked to anxiety,^11-16 as well as inflammation.

An increase in inflammatory markers is common in patients with anxiety disorders.^17,18 One review looked at patients with PTSD and found an increase in IL-6, TNF-alpha and other inflammatory markers.¹⁹ To quote one researcher, “Overall, inflammation causes disruptions in the blood-brain barrier along with cellular and structural changes within the CNS. In vitro and in vivo animal models have shown that inflammation decreases neurogenesis in the hippocampus, induces glutamate release from microglia and impairs LTP. Human MRI studies have shown IFNα and endotoxin treatments result in rapid changes in white matter structure, brain global connectivity and functional activation, all of which are linked to depression and fatigue.²⁰”

The link between depression and inflammation is perhaps stronger. One study looked at CRP levels in patients with major depressive disorder. Researchers found that high CRP levels made patients less responsive to treatment. High levels were also associated with cognitive impairment (which the antidepressant treatment did not affect).²¹ Another study found a strong correlation between high IL-6 and CRP levels with depression. Patients with depression had higher levels of these inflammatory markers than did healthy controls.²²

Anxiety and inflammation

We know anxiety and inflammation are associated. Does anxiety cause inflammation or does inflammation cause anxiety? Or both? It turns out creating inflammation produces anxiety. Lipopolysaccharide is a component of the cell membrane of gram-negative bacteria, and it reliably induces an inflammatory response. Lipopolysaccharide was injected into 186 healthy volunteers. The injections produced both an increase in inflammatory markers and anxiety.²³ The subjects with the greatest increase in IL-6 experienced the greatest increase in anxiety.

The gut microbiome

One source of both inflammation and anxiety may be the gut microbiome. The makeup of the bacteria in our intestines can have an effect on mental health. The gut microbiome

can affect inflammation, depression and anxiety.²⁴ There is a great deal of interest in the gut-brain axis, which is bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions.²⁵ The GI can be the source of inflammation. Research has shown the makeup of the microbiota can play a role in anxiety and depression.^26,27

Final thoughts

Patients spend around $18 billion each year on anxiety medications (around $1300 per person). There has been a 13% increase in mental health conditions in the last decade. By addressing the root causes of these conditions, such as stress, inflammation and bowel ecology, DCs can recommend the right treatment plan to help improve their patient’s quality of life.

PAUL VARNAS, DC, DACBN, is a graduate of the National College of Chiropractic and has had a functional medicine practice for 34 years. He has authored several books and taught nutrition at the National University of Health Sciences. For a free PDF of “Instantly Have a Functional Medicine Practice” or a patient handout on the anti-inflammatory diet, email him at paulgvarnas@gmail.com.

REFERENCES

1. Patriquin MA, Mathew SJ. The neurobiological mechanisms of generalized anxiety disorder and chronic stress. Chronic Stress (Thousand Oaks). 2017;1:2470547017703993. PubMed website. https://pubmed.ncbi.nlm.nih.gov/29503978/. Accessed Oct. 5, 2023.
2. Lin E, Tsai SJ. Gene-environment interactions and role of epigenetics in anxiety disorders. Adv Exp Med Biol. 2020;1191:93–102. PubMed website. https://pubmed.ncbi.nlm.nih.gov/32002924/. Accessed Oct. 5, 2023.
3. Conway CC, et. al. Chronic environmental stress and the temporal course of depression and panic disorder: A trait-state-occasion modeling approach. J Abnorm Psychol. 2016;125(1):53–63. PubMed website. https://pubmed.ncbi.nlm.nih.gov/26595465/. Accessed Oct. 5, 2023.
4. Wade SL, et. al. Chronic life stress and treatment outcome in agoraphobia with panic attacks. Am J Psychiatry. 1993;150(10):1491–1495. PubMed website. https://pubmed.ncbi.nlm.nih.gov/8379552/. Accessed Oct. 5, 2023.
5. Op cit 1.
6. Won E, Kim YK. Neuroinflammation-associated alterations of the brain as potential neural biomarkers in anxiety disorders. Int J Mol Sci. 2020 Sep; 21(18): 6546. PubMed website. https://pubmed.ncbi.nlm.nih.gov/32906843/. Accessed Oct. 5, 2023.
7. Norman M, Hearing SD. Glucocorticoid resistance—What is known? Curr Opin Pharmacol. 2002;2(6):723–729. PubMed website. https://pubmed.ncbi.nlm.nih.gov/12482737/. Accessed Oct. 5, 2023.
8. Sorrells SF, et. al. The stressed CNS: When glucocorticoids aggravate inflammation. 2009;64(1):33–39. PubMed website. https://pubmed.ncbi.nlm.nih.gov/19840546/. Accessed Oct. 5, 2023.
9. Yang N, et. al. Current concepts in glucocorticoid resistance. 2012;77(11):1041–1049. PubMed website. https://pubmed.ncbi.nlm.nih.gov/22728894/. Accessed Oct. 5, 2023.
10. Gustavson SM, et. al. Stimulation of both type I and type II corticosteroid receptors blunts counterregulatory responses to subsequent hypoglycemia in healthy man. Am J Physiol. Endocrinol Metab. 2008;294(3):E506–E512. PubMed website. https://pubmed.ncbi.nlm.nih.gov/18182467/. Accessed Oct. 5, 2023.
11. Condren RM, et. al. HPA axis response to a psychological stressor in generalised social phobia. 2002;27(6):693–703. PubMed website. https://pubmed.ncbi.nlm.nih.gov/12084662/. Accessed Oct. 5, 2023.
12. Schreiber W, et. al. Dysregulation of the hypothalamic-pituitary-adrenocortical system in panic disorder. 1996;15(1):7–15. PubMed website. https://pubmed.ncbi.nlm.nih.gov/8797187/. Accessed Oct. 5, 2023.
13. Erhardt A, et. al. Regulation of the hypothalamic-pituitary-adrenocortical system in patients with panic disorder. 2006;31(11):2515–2522. PubMed website. https://pubmed.ncbi.nlm.nih.gov/16841071/. Accessed Oct. 5, 2023.
14. Griffin MG, et. al. Enhanced cortisol suppression following dexamethasone administration in domestic violence survivors. Am J Psychiatry. 2005;162(6):1192–1199. PubMed website. https://pubmed.ncbi.nlm.nih.gov/15930069/. Accessed Oct. 5, 2023.
15. Risbrough VB, Stein MB. Role of corticotropin releasing factor in anxiety disorders: A translational research perspective. Horm Behav. 2006;50(4):550–561. Science Direct. https://www.sciencedirect.com/science/article/pii/S0018506X0600170X. Accessed Oct. 5, 2023.
16. Zorn JV, et. al. Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis. 2017;77:25–36. PubMed website. https://pubmed.ncbi.nlm.nih.gov/28012291/. Accessed Oct. 5, 2023.
17. Pitsavos C, et. al. Anxiety in relation to inflammation and coagulation markers, among healthy adults: The ATTICA Study. 2006;185(2):320-6. PubMed website. https://pubmed.ncbi.nlm.nih.gov/16005881/. Accessed Oct. 5, 2023.
18. Michopoulos V, et. al. Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond. 2017;42(1):254-270. PubMed website. https://pubmed.ncbi.nlm.nih.gov/27510423/. Accessed Oct. 5, 2023.
19. Passos IC, et. al. Inflammatory markers in post-traumatic stress disorder: A systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2(11):1002-12. PubMed website. https://pubmed.ncbi.nlm.nih.gov/26544749/. Accessed Oct. 5, 2023.
20. Lee CH, Giuliani F. The role of inflammation in depression and fatigue. Front Immunol. 2019;10:1696. PubMed website. https://pubmed.ncbi.nlm.nih.gov/31379879/. Accessed Oct. 5, 2023.
21. Chang HH, et. al. Treatment response and cognitive impairment in major depression: Association with C-reactive protein. Brain Behav Immun. 2012;26(1):90-5. PubMed website. https://pubmed.ncbi.nlm.nih.gov/21839826/. Accessed Oct. 5, 2023.
22. Krogh J, et. al. The association between depressive symptoms, cognitive function, and inflammation in major depression. Brain Behav Immun. 2014;35:70-6. PubMed website. https://pubmed.ncbi.nlm.nih.gov/24016864/. Accessed Oct. 5, 2023.
23. Lasselin J, et. al. Mood disturbance during experimental endotoxemia: Predictors of state anxiety as a psychological component of sickness behavior. Brain Behav Immun. 2016;57:30-37. PubMed website. https://pubmed.ncbi.nlm.nih.gov/26790758/. Accessed Oct. 5, 2023.
24. Peirce JM, Alvina K. The role of inflammation and the gut microbiome in depression and anxiety. J Neurosci Res. 2019;97(10):1223-1241. PubMed website. https://pubmed.ncbi.nlm.nih.gov/31144383/.Accessed Oct. 5, 2023.
25. Carabotti M, et. al. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203–209. PubMed website. https://pubmed.ncbi.nlm.nih.gov/25830558/. Accessed Oct. 5, 2023.
26. Foster JA, McVey Neufeld KA. Gut-brain axis: How the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–312. PubMed website. https://pubmed.ncbi.nlm.nih.gov/23384445/. Accessed Oct. 5, 2023.
27. Naseribafrouei A, et. al. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil. 2014;26(8):1155–1162. PubMed website. https://pubmed.ncbi.nlm.nih.gov/24888394/Accessed Oct. 5, 2023.