Collagen Peptide Supplementation in Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders: Gene-Independent Mechanisms in Fascia, Peripheral Nerve, and Extracellular Matrix — A Hypothesis-Generating Review

Clinical guidance widely advises people with Ehlers-Danlos syndrome and hypermobility spectrum disorders that collagen supplements cannot help, asserting that supplemental collagen is degraded during digestion and that genetic mutations make stimulating synthesis futile. This narrative review evaluates whether published biochemical and genetic evidence supports either claim. Human pharmacokinetic data show that bioactive dipeptides, including Pro-Hyp and Hyp-Gly, survive digestion and reach systemic circulation. However, achievable plasma concentrations reach roughly 20 to 33 micromoles per liter, leaving an unresolved translational gap compared to the 200 micromoles per liter threshold required for cellular activation in laboratory models. The review identifies multiple gene-independent mechanisms and outlines six falsifiable hypotheses spanning substrate depletion, small fiber neuropathy, hair follicle hydrogel loss, mast cell regulation, fascial catabolic loop interruption, and degradative environment correction across tendon, perineurium, vascular adventitia, and basement membrane compartments. Furthermore, genetic analysis reveals that blanket dismissal conflates haploinsufficiency with dominant-negative trimer poisoning seen in structural subtypes like vascular Ehlers-Danlos syndrome, carrying least justification in hypermobile Ehlers-Danlos syndrome where structural collagen mutations remain unidentified. Supported by 59 references with transparent annotations of industry-affiliated citations, this paper does not recommend supplementation, any dose, or any regimen, and is not medical advice.