Welcome to the PGE2 Hypothesis website

We would like to highlight several observations from the scientific literature.

Triggers associated with chronic fatigue syndromes including LC/PAIS/ME/CFS, whether physical or psychological stressors, are reported to stimulate PGE2 production. PGE2 is a major mediator of the “sickness response”, producing familiar symptoms such as fever, inflammation, gastrointestinal problems, pain and fatigue.

PGE2 is a single signaling molecule, but it acts through four highly versatile receptors, EP1–EP4, which can exert distinct and often opposing effects. Our literature review revealed that the known functions of these receptors correspond strikingly well with the diverse biological disturbances and symptomclusters reported in Long COVID (LC) and related syndromes. PubMed searches repeatedly identified roles for PGE2 in symptoms and comorbidities and mechanisms associated with fatigue syndromes. We therefore propose that PGE2 may remain persistently upregulated in patients who develop LC or other chronic fatigue syndromes.

Because EP-receptor expression varies between tissues and individuals, different expression profiles could potentially produce very different phenotypes. Techniques are available to investigate the expression of all four EP receptors and determine whether such profiles differ between patients.

This leads to a testable hypothesis. If persistent PGE2 upregulation and altered EP-receptor expression contribute to Long COVID and related syndromes, these patterns should be detectable and should correspond to specific clinical and biological features.

If validated, the hypothesis could help explain the variable results of clinical trials and, importantly, why a treatment may benefit one patient, have no effect in another, or even make someone worse. It could also provide molecular biomarkers for patient stratification, potentially helping to identify which treatments are most suitable for which patient subtypes.

This is why we are looking for researchers interested in testing the hypothesis.

In brief, research shows that many hormones and other signaling molecules stimulate PGE2 production, while PGE2 can in turn modulate their production or signaling. We hypothesize that, under certain conditions, these reciprocal feedback mechanisms could contribute to persistent PGE2 upregulation, altered EP-receptor signaling, autoimmune responses, resistances, ensuing chronic PGE2 upregulation and chronic illness.

The scientific basis and references for this hypothesis are presented in our recently published article in Biochemistry and Biophysics Report