Hypermobile Ehlers-Danlos Syndrome (hEDS) has long been considered a primarily genetic condition—one characterized by joint hypermobility, tissue fragility, and a wide range of systemic symptoms.

Yet unlike other forms of EDS, hEDS has no single confirmed genetic marker. Diagnosis remains clinical, based on patterns of hypermobility, skin findings, and associated symptoms (1).

This gap has led to an important question:

Is hEDS purely genetic—or could it represent a more complex interaction between genetic susceptibility and environmental triggers?

Emerging research suggests the latter may be worth serious consideration.

What Is hEDS, Really?

At its core, hEDS is a disorder of connective tissue, particularly involving collagen—the structural protein that provides strength and elasticity to ligaments, tendons, skin, and blood vessels (1).

Patients with hEDS often experience joint hypermobility, chronic pain, dysautonomia, and gastrointestinal dysfunction. Traditionally, these features have been attributed to inherited abnormalities in collagen structure or regulation. However, the absence of a consistent genetic mutation in hEDS suggests that the condition may involve more complex biological mechanisms.

The Genetic Piece: Real, But Incomplete

Recent research, including findings from the HEDGE (Hypermobile Ehlers-Danlos Genetic Evaluation) study, has begun to identify previously unrecognized genetic variants and patterns associated with hEDS (2,3).

Rather than identifying a single causative mutation, these findings support a model in which:

• Multiple genetic variants contribute modest effects
• Connective tissue integrity is influenced by complex regulatory pathways

This points toward a polygenic and heterogeneous condition, where genetics establish susceptibility but do not fully determine disease expression.

A Two-Hit Model: Genetic Susceptibility + Environmental Triggers

An increasingly plausible framework is that hEDS may reflect a two-hit model:

1. Underlying connective tissue susceptibility
2. Environmental or biological triggers that disrupt tissue integrity

These triggers may include chronic inflammation, immune dysregulation, toxins, or infections.

Among these, chronic infections—particularly vector-borne infections—have drawn growing attention.

Can Infections Affect Connective Tissue?

Collagen is a dynamic structure that is constantly remodeled through the balance of synthesis and degradation. This process is regulated by fibroblasts, matrix metalloproteinases (MMPs), and immune signaling pathways (4).

Chronic inflammation can disrupt this balance by:

• Increasing MMP activity (collagen breakdown)
• Altering fibroblast function
• Sustaining cytokine signaling that impairs tissue repair

This provides a biological basis for infection-related effects on connective tissue.

Bartonella and Connective Tissue

Bartonella species are increasingly recognized for their ability to infect endothelial cells and contribute to chronic inflammatory states (5).

Clinical studies have documented rheumatologic manifestations in patients with Bartonella henselae and Bartonella koehlerae bacteremia, including joint pain, tendon involvement, and connective tissue symptoms (5).

Notably, investigators have proposed that Bartonella species may:

• Interact with collagen-rich tissues
• Contribute to progressive connective tissue dysfunction through chronic inflammation

While further research is needed, this raises the possibility that Bartonella infection may act as a modifier of connective tissue disease expression.

Borrelia burgdorferi and Tissue Integrity

Borrelia, the causative agent of Lyme disease, has a well-documented ability to:

• Disseminate through connective tissue
• Bind to extracellular matrix components
• Alter host immune responses (6)

Experimental and clinical observations suggest that Borrelia infection may:

• Influence collagen turnover
• Promote inflammatory pathways associated with tissue degradation (6)

Emerging clinical data, including findings from the MAESTRO study, have reported associations between prior Borrelia infection and features of hypermobility disorders in individuals with persistent symptoms (7).

Although these findings are preliminary, they raise important questions about whether infection may contribute to connective tissue changes in susceptible individuals.

Connecting This Back to hEDS

Taken together, these observations support a model in which:

• Genetic susceptibility creates a baseline vulnerability
• Chronic infections contribute to immune dysregulation and inflammation
• Collagen homeostasis becomes disrupted over time

This may lead to progressive joint instability, tendon dysfunction, and chronic pain syndromes that resemble or overlap with hEDS.

Importantly, this does not imply that infections “cause” hEDS in a traditional sense. Rather, they may unmask or amplify an underlying susceptibility.

Why This Matters Clinically

If hEDS is viewed as purely genetic and static, treatment is largely supportive.

However, if environmental factors contribute to disease expression, this suggests that:

• Addressing chronic infections
• Reducing inflammation
• Supporting connective tissue repair

may influence symptoms in selected patients.

This expands the clinical framework beyond symptom management alone.

A Word of Caution

This area remains under active investigation.

• There is no definitive evidence that infections cause hEDS
• Not all patients with hEDS have evidence of chronic infection
• The relationship is likely heterogeneous

However, the overlap between chronic infection, immune dysregulation, and connective tissue dysfunction warrants further study.

Final Perspective

Hypermobile EDS may represent a spectrum of connective tissue dysfunction, influenced by both genetic predisposition and environmental factors.

For some individuals, chronic infections such as Bartonella and Borrelia may act as modifiers of disease expression, contributing to symptom severity and progression.

A more integrated model—incorporating both genetics and environmental triggers—may ultimately provide a more complete understanding of this complex condition.

References

1. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8–26.
2. Levy HP. Hypermobile Ehlers-Danlos syndrome. GeneReviews. 2023.
3. Ehlers-Danlos Society. The HEDGE Study. Available at: https://www.ehlers-danlos.com/the-hedge-study/
4. Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev. 2016;97:4–27.
5. Breitschwerdt EB, Maggi RG, Nicholson WL, et al. Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias. PLoS One. 2018;13(3):e0193789.
6. Cabello FC, Godfrey HP, Bugrysheva J, Newman SA. Molecular architecture of Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22(2):205–228.
7. MAESTRO Study (Borrelia burgdorferi and connective tissue outcomes). J Immunol. 2024;214(Supplement_1):vkaf283.1711.

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