The causes of Fibromyalgia – latest theories (2025)

 

Fibromyalgia remains one of the most enigmatic chronic pain disorders, yet in 2025 our understanding is growing deeper through multiple converging research directions. Rather than a single cause, fibromyalgia appears to arise from an interaction of genetic susceptibility, nervous system dysregulation, immune activity, metabolic and mitochondrial dysfunction, gut microbiome imbalance, and environmental triggers. Collectively these emerging theories offer a more holistic understanding of the origins of the syndrome.

One of the primary explanations is central sensitization, a condition in which the brain and spinal cord amplify pain signals. Neuroimaging studies reveal heightened activity in regions such as the insula, anterior cingulate cortex, thalamus, and somatosensory cortex. At the same time, inhibitory pain pathways are diminished, creating a neurological environment where even gentle touch becomes painful. Neurotransmitter imbalances—elevated substance P and glutamate, reduced serotonin, dopamine and norepinephrine—further fuel symptom severity. Brain connectivity patterns are altered and less stable, correlating with increased pain, fatigue and cognitive symptoms.

Parallel to this, immune system theories now play a central role. Growing evidence supports low‑grade systemic and neuroinflammation in people with fibromyalgia. Elevated levels of cytokines such as IL‑6, IL‑8, TNF‑α and C‑reactive protein connect pain amplification with immune signaling shifts. Recent breakthrough studies demonstrate that autoantibodies derived from fibromyalgia patients can induce pain hypersensitivity and muscle weakness in animal models. This supports a model where immune dysfunction, possibly involving dysfunctional mast cell activity and antibody‑mediated inflammatory complexes, links peripheral tissue changes to central nervous system hyperexcitability.

Among peripheral mechanisms, small‑fiber neuropathy is increasingly recognized. Skin biopsies in a substantial subset of fibromyalgia patients show reduced density of intraepidermal nerve fibers. These damaged small nerve fibers transmit pain and sensory signals and may contribute to heightened pain sensitivity and autonomic dysfunction. Abnormalities in fascia and muscle tissue, such as elevated oxidative stress markers and increased intramuscular pressure, may compound pain through sympathetic nervous system overactivity, impaired healing, and immune complex formation causing inflammation in dorsal root ganglia.

Metabolic and mitochondrial dysfunction continue to gain attention. Mitochondria in muscle and neural tissue appear underperforming, with decreased energy output, heightened oxidative stress, lipid peroxidation and compromised DNA or enzyme function. These deficits may trigger proinflammatory cytokine release and correspond with fatigue, pain, and intolerance of activity. Some interventions targeting mitochondrial support—such as Coenzyme Q10, malic acid or D‑ribose supplementation—report modest symptom improvements.

Genetic predisposition also remains a strong contributor. Heritability may account for up to half of fibromyalgia risk. Variants in genes regulating neurotransmitters, pain signaling, stress response and inflammation—including COMT, serotonin receptors, dopamine receptors, and TNF pathways—appear more common in affected individuals. In many cases, epigenetic modifications triggered by trauma, infection, or prolonged stress alter gene expression patterns in nociceptive circuits, decreasing pain thresholds and increasing vulnerability.

Environmental and psychosocial factors often serve as triggers. Many individuals report a history of physical or emotional trauma, childhood adversity, grief or injury preceding the onset of symptoms. Infectious events, including viral illnesses such as Epstein‑Barr or COVID‑19, are commonly cited as catalysts. Chronic stress over time dysregulates the hypothalamic‑pituitary‑adrenal axis and sympathetic nervous system, impairing cortisol rhythms and autonomic regulation, promoting persistent systemic and neuro inflammation.

The gut‑brain axis is another emerging frontier. People with fibromyalgia often show reduced diversity in gut microbiota and shifts toward pro‑inflammatory bacterial species. These changes influence immune signaling, neurotransmitter metabolism, and the vagal nervous system. Preliminary evidence even suggests that fecal microbiota transplantation may modestly reduce pain, improve fatigue and enhance function, though larger trials are needed.

All of these individual mechanisms fit within the broader concept of nociplastic pain: pain arising not from tissue damage or inflammation alone, but from aberrant signal processing in the nervous system. Nociplastic pain is triggered and maintained through complex interactions among peripheral and central circuits, immune modulation, metabolic insufficiency, gut and genetic factors, and psychosocial stressors. Novel models such as the FITSS (imbalance between threat and soothing neural systems) model propose persistent overactivity of brain regions responsible for threat detection and diminished soothing pathways, creating chronic hypervigilance and pain amplification.

Advanced multiomics research—incorporating transcriptomics, proteomics, metabolomics—and artificial intelligence are now being applied to large datasets of clinical, neuroimaging, genetic, metabolic and environmental information. These approaches aim to identify biomarkers and patterns that classify fibromyalgia subtypes, predict treatment response and guide precision therapy. Early results suggest there may be distinct clusters of patients dominated by immune‑driven inflammation, mitochondrial dysfunction, central sensitization or gut microbiome disruption.

In summary, the causes of fibromyalgia in 2025 are best understood as multifactorial and heterogeneous. The latest evidence supports an interplay between:

• hypersensitive central pain processing
• immune dysregulation and neuroinflammation
• small‑fiber nerve pathology
• mitochondrial and metabolic dysfunction
• genetic/epigenetic vulnerability
• gut microbiome imbalance
• environmental stressors including trauma and infection

This integrated view holds promise for more personalized diagnosis and treatment. Blood‑based biomarker panels, autoantibody assays, neuroimaging patterns and gut microbiota signatures may eventually be used clinically to stratify patients and target therapies such as immune modulators, mitochondrial support, brain retraining, microbiome interventions or neuroplasticity‑based rehabilitation.

As research continues through 2025 and beyond, fibromyalgia is evolving from a diagnosis of exclusion into a condition with identifiable biological underpinnings that vary across individuals. Understanding these latest theories brings hope for tailored approaches that address the root drivers of pain and dysfunction, rather than just managing symptoms.

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