Inflammatory Bowel Disease and Ehlers-Danlos Syndrome

Inflammatory Bowel Disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is classically recognized as a chronic immune-mediated condition of the gastrointestinal tract. Yet for many patients, symptoms extend far beyond the gut.

A growing body of evidence suggests a surprising overlap between IBD and joint hypermobility disorders—including the hypermobile subtype of Ehlers-Danlos syndrome (hEDS). This intersection spans the gastrointestinal, musculoskeletal, and immune systems, posing challenges for diagnosis and management while offering insights into shared underlying mechanisms.

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For a deeper dive into GI issues in EDS, read "The Comprehensive Guide to Gastrointestinal Issues in Ehlers-Danlos Syndrome:" from The EDS Clinic.

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Types of Inflammatory Bowel Disease

IBD refers to two main chronic disorders: Crohn’s disease and ulcerative colitis, both of which cause inflammation in the gastrointestinal (GI) tract, but differ in their location, depth, and clinical complications.

Crohn’s Disease (CD)

• Can affect any part of the GI tract, from mouth to anus
• Most commonly involves the terminal ileum and colon
• Inflammation is transmural and occurs in patchy segments
• Associated with complications like fistulas, strictures, malabsorption, and perianal disease

Ulcerative Colitis (UC)

• Confined to the colon, starting in the rectum and extending proximally
• Inflammation is continuous and limited to the mucosal layer
• Symptoms often include bloody diarrhea, urgency, and abdominal cramping
• Severe cases may result in toxic megacolon or necessitate colectomy

Indeterminate Colitis / IBD-Unclassified

• In some patients, the disease cannot be clearly classified as either CD or UC
• This condition is referred to as indeterminate colitis or IBD-U

Both conditions are thought to arise from a dysregulated immune response in genetically predisposed individuals, often triggered by environmental or microbial factors.

Joint Hypermobility in IBD: Underestimated and Underdiagnosed

A landmark study by Vounotrypidis et al. (2009) found that 70.7% of Crohn’s patients and 35.7% of UC patients met criteria for joint hypermobility, compared to just 25.4% of controls. The odds ratio for hypermobility in Crohn’s disease was strikingly high (OR: 7.1), suggesting a substantial enrichment of hypermobility traits among this population.

While the pathophysiological link remains unclear, the study emphasized that musculoskeletal symptoms in IBD patients with joint hypermobility are frequently misdiagnosed or overlooked, leading to inappropriate treatments and delayed recognition of connective tissue involvement.

Ehlers-Danlos Syndrome and the GI Tract

Ehlers-Danlos Syndrome (EDS) comprises a group of inherited connective tissue disorders, primarily characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Among its subtypes, hypermobile EDS (hEDS) is the most prevalent but lacks a definitive genetic test.

GI symptoms are increasingly recognized in hEDS. Studies by Fikree et al. (2017) and Alomari et al. (2020) have shown that more than 60% of patients with hEDS report gastrointestinal issues such as nausea, bloating, abdominal pain, constipation, and diarrhea. Among those who underwent motility testing, 76% were found to have measurable GI dysmotility, including gastroparesis and colonic transit delay.

A recent article from The EDS Clinic further details this relationship, explaining how gastroparesis and intestinal pseudo-obstruction are frequently misdiagnosed or mistreated in patients with hEDS and POTS (Postural Orthostatic Tachycardia Syndrome).

Moreover, the presence of POTS has been shown to increase the likelihood of GI dysmotility by more than five times (Alomari et al., 2020).

Musculoskeletal Manifestations in IBD

Musculoskeletal symptoms are the most common extraintestinal manifestation of IBD, affecting up to 46% of patients (Bourikas & Papadakis, 2009). These include:

• Peripheral arthritis, which may be Type I (pauciarticular, flare-related) or Type II (polyarticular, chronic, independent of gut disease)
• Axial arthritis, such as sacroiliitis and ankylosing spondylitis
• Enthesitis, tenosynovitis, and dactylitis, often resembling seronegative spondyloarthropathies

These musculoskeletal manifestations often precede IBD diagnosis and may clinically overlap with hypermobility-related syndromes, especially when patients report diffuse pain or stiffness.

Cytokines and Shared Mechanisms

Immunological overlap between IBD and EDS-like conditions has also been explored. In a study by Vounotrypidis et al. (2013), levels of IL-1α were found to correlate with Crohn’s disease activity, while IL-1β and IL-1Ra were elevated in ulcerative colitis. These cytokines also played a role in patients with enteropathic arthritis.

These findings support a shared inflammatory signature between gut inflammation and musculoskeletal involvement. Mechanisms such as barrier dysfunction, dysbiosis, and connective tissue matrix abnormalities may contribute to both GI and MSK symptomatology in susceptible individuals.

Clinical Implications: Bridging Disciplines

The under-recognition of hypermobility in IBD patients has real clinical consequences. Patients may undergo repeated endoscopies, unnecessary medication escalation, or even surgery—when their symptoms are actually rooted in dysmotility, autonomic dysfunction, or connective tissue fragility.

Conversely, hEDS patients with GI complaints may be misdiagnosed with IBD, despite lacking histologic evidence of inflammation. The presence of POTS or mast cell activation symptoms may further complicate the clinical picture.

A multidisciplinary care model—including gastroenterologists, rheumatologists, geneticists, physiatrists, and neurologists—is crucial. Early recognition of hypermobility and autonomic symptoms can reduce iatrogenic harm and guide more effective, individualized care.

Knowledge Gaps and Future Directions

While a growing number of studies point to this overlap, key questions remain unanswered:

• How common is hEDS in the IBD population, and vice versa?
• Are there shared genetic or epigenetic pathways?
• What is the natural history of patients with both disorders?
• Can tailored treatment strategies improve outcomes in patients with overlapping syndromes?

Large, prospective studies are needed to define the overlap more clearly and guide evidence-based practice.

Conclusion

The overlap between IBD and hypermobility syndromes like hEDS is real, under-recognized, and clinically significant. For patients experiencing both gut and joint symptoms, understanding this connection can open the door to better care—and relief.

As evidence continues to emerge, collaboration between specialties will be essential to provide comprehensive, compassionate care for these complex patients.

References

Alomari, M., Hitawala, A., Chadalavada, P., Covut, F., Al Momani, L., Khazaaleh, S., Gosai, F., Al Ashi, S., Abushahin, A., & Schneider, A. (2020). Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience. Cureus, 12(4), e7881. https://doi.org/10.7759/cureus.7881

Bourikas, L. A., & Papadakis, K. A. (2009). Musculoskeletal manifestations of inflammatory bowel disease. Inflammatory Bowel Diseases, 15(12), 1915–1924. https://doi.org/10.1002/ibd.20942

Fikree, A., Chelimsky, G., Collins, H., Kovacic, K., & Aziz, Q. (2017). Gastrointestinal involvement in the Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), 181–187. https://doi.org/10.1002/ajmg.c.31546

The EDS Clinic. (2023). Gastrointestinal Disorders in Ehlers-Danlos Syndrome and POTS. Retrieved from https://www.eds.clinic/articles/gastrointestinal-disorders-in-ehlers-danlos-syndrome-and-pots

The EDS Clinic. (2023). EDS and Gastroparesis. Retrieved from https://www.eds.clinic/articles/eds-and-gastroparesis

Vounotrypidis, P., Efremidou, E., Zezos, P., Pitiakoudis, M., Maltezos, E., Lyratzopoulos, N., & Kouklakis, G. (2009). Prevalence of Joint Hypermobility and Patterns of Articular Manifestations in Patients with Inflammatory Bowel Disease. Gastroenterology Research and Practice, 2009, 924138. https://doi.org/10.1155/2009/924138

Vounotrypidis, P., Kouklakis, G., Anagnostopoulos, K., Zezos, P., Polychronidis, A., Maltezos, E., Efremidou, E., Pitiakoudis, M., & Lyratzopoulos, N. (2013). Interleukin-1 associations in inflammatory bowel disease and the enteropathic seronegative spondylarthritis. Autoimmunity Highlights, 4(3), 87–94. https://doi.org/10.1007/s13317-013-0049-4

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