The classification criteria for fibromyalgia have changed over time, affecting its definition from a “peripheral pain-defined disease” to a “systemic symptom-based disease.” Indeed, the ACR-2010 established a widespread pain index, replacing the previous 18 specified tender points. In addition, the new criteria assess the severity of three significant extra-pain symptoms of fatigue, sleep disturbance, and cognitive impairments. These critical factors, along with symptoms like diffuse stiffness, irritable bowel syndrome, memory issues, brain fog, numbness, depression, dizziness, and temporomandibular joint dysfunction, overlap, and link with autoimmune disease and neuroinflammation. Consequently, the environmental causes of autoimmune reactions lead to neuroinflammation resulting in worsening symptoms of fibromyalgia.

Autoimmunity, Infection, and fibromyalgia

Studies show a connection between trauma and infection as triggers of fibromyalgia flare-up. Furthermore, this creates an association between autoimmunity and FM pathogenesis. Specifically, pathogens like Epstein-Barr virus, Herpes simplex virus, hepatitis virus C, and Borrelia burgdorferi directly associate with FM symptomatology. Furthermore, other common situations related to FM are silicon implants, vaccination, and mineral oil injection. 

Research shows a higher prevalence of FM on those patients with B58, DR5, and DR8 HLA alleles regarding genetic associations. However, these genetic variants have an overlapping link with autoimmune disease leading to rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjogren’s syndrome, vasculitis, polymyositis, spondylarthritis, inflammatory bowel diseases, celiac disease, and diabetes mellitus type 1. 

Additionally, the activation of the adaptive immune system is affected directly by the patient’s immune cell profile. Indeed, the increase of all B lymphocyte subsets, CD4+CD25 low, activates lymphocytes and NK cells are crucial in the onset of FM.

Furthermore, a common finding is elevated levels of autoantibodies in the sera of FM patients. The autoantibodies commonly found in the sera of females FM patients are anti-smooth muscle AAb and anti-strained muscle AAb. 


Neuroinflammation plays a crucial role in linking the inflammatory mechanisms to FM’s chronic pain condition, probably triggering central sensitization.

Furthermore, the measurement and analysis of several inflammatory proteins in the cerebrospinal fluid (CFS) and plasma are significantly associated with neuroinflammation and chronic systemic inflammation. Indeed, fractalkine, also known as CX3CL1, is a chemokine serving as a signal of neuropathic pain elevated in CFS and plasma. 

Recent studies on mice have shown that the use of Morpholinurea-leucine-homophenylalanine-vinyl sulfone-phenyl (LHVS) inhibits cathepsin S and stops the increase of fractalkine. Also, the treatment of mice with LHVS has significantly attenuated autoimmune encephalitis and multiple sclerosis.

Adding to these benefits, LHVS therapy has been shown to reverse pain behavior in collagen-induced arthritis, rheumatoid arthritis in animal-based models. Furthermore, mechanical pressure hypersensitivity, autoimmune myositis in animal models show significant reduction with LHVS therapy.

Consistent with these results, several inflammatory cytokines have shown a reduction after LHVS therapy. Indeed, a decrease of IFNy, IL-3, IL-5, and IL-13 cytokines

  • Microglia activation:

Positron emission tomography in the cortex of patients previously diagnosed with FM has evidenced the presence of activated microglia, specifically in the medial and lateral walls of the frontal and parietal lobes.

In addition, subjective reports of fatigue are associated directly with higher microglial activation in the anterior and posterior cortices.

Neuroinflammation is a critical factor in fibromyalgia onset condition, which is associated with stress and pain. Nevertheless, secondary factors such as small bacterial intestine overgrowth, vitamin D deficiency, and mitochondrial dysfunction overlap with this condition aggravating the disease. Consequently, these factors contribute to their associated or triggered diseases, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

Fibromyalgia and Gastrointestinal issues:

Fibromyalgia’s nutritional treatment should focus on reducing gastrointestinal inflammation and supplementing vitamins. Therefore, a comprehensive assessment of the gastrointestinal tract is crucial. In El Paso Functional Medicine, we use integrative medicine tests to evaluate the patient’s condition.


As neuroinflammation and autoimmune disorders overlap within the diagnosis of FM, chiropractic and medical-nutritional therapy have to be part of this disease’s treatment. Indeed, as the diagnosis of FM, IBS, SIBO, and IBD are more frequent in females than in males, the nutritional component has to be managed by careful assessment of food sensitivities and followed with a low FODMAP or elimination diet. Furthermore, both of these treatments need to be reassessed for food reintroduction.- Ana Paola Rodriguez Arciniega, MS


Ryabkova, Varvara A et al. “Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?.” International journal of molecular sciences vol. 20,20 5164. 18 Oct. 2019, doi:10.3390/ijms20205164

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The information herein on "Pain Brain: Neuroinflammation and Fibromyalgia" is not intended to replace a one-on-one relationship with a qualified health care professional or licensed physician and is not medical advice. We encourage you to make healthcare decisions based on your research and partnership with a qualified healthcare professional.

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