Introduction
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by collagen abnormalities that frequently involve the gastrointestinal tract. Patients with EDS commonly report symptoms consistent with disorders of gut-brain interaction, including irritable bowel syndrome (IBS); however, population-level evidence quantifying this association remains limited. Furthermore, psychological comorbidities such as anxiety are highly prevalent in EDS and may contribute to gastrointestinal symptom development, yet their potential mediating role in the relationship between EDS and IBS has not been well characterized. We therefore conducted a large national inpatient database analysis to evaluate the association between EDS and IBS and to explore the contribution of anxiety as a potential mediator.
Aims & Methods
We performed a retrospective study using the 2019 National Inpatient Sample (NIS) database to identify hospitalizations involving EDS and IBS using ICD-10 diagnostic codes, including hypermobility spectrum disorder classifications. Demographic characteristics, comorbidities, and socioeconomic variables were analyzed. Multivariable logistic regression models were constructed to evaluate the association between EDS and IBS while adjusting for potential confounders. Subgroup analyses were performed according to IBS subtype. Structural equation modeling (SEM) was applied to assess anxiety as a mediator between EDS and IBS. Statistical analyses were conducted using Stata 15.1 and R 4.5.2.
Results
An estimated 35,419,023 hospitalizations were analyzed, including 14,675 EDS cases and 320,635 IBS cases. Patients with EDS were younger (mean age 36.2 vs. 50.2 years), predominantly female (84.8% vs. 55.8%), and demonstrated higher prevalence of psychiatric and gastrointestinal comorbidities. EDS was strongly associated with IBS across regression models, with odds ratios (ORs) of 7.66 (95% CI: 6.56 - 8.95) in crude analysis, 5.80 (95% CI: 4.92 - 6.83) after adjustment for demographics and socioeconomic factors, 4.96 (95% CI: 4.20 - 5.86) after inclusion of gastrointestinal and psychiatric diagnoses, and 4.16 (95% CI: 3.50 - 4.93) in the fully adjusted model. The strongest association was observed for IBS with constipation (OR 7.80, 95% CI: 5.19 - 11.71), followed by mixed subtype (OR 5.34, 95% CI: 2.35 - 12.15) and unspecified IBS (OR 3.57, 95% CI: 2.92 - 4.36). Anxiety was present in 36.16% of IBS and 32.65% of EDS cases. SEM analysis demonstrated that anxiety partially mediated the EDS-IBS relationship, accounting for approximately 6.6% of the total effect, while the majority of the association remained attributable to direct effects.
Conclusion
EDS is strongly associated with IBS, particularly constipation-predominant disease, in a large national inpatient cohort. Anxiety partially mediates this relationship but does not fully explain the observed association, suggesting that connective tissue abnormalities and altered gut-brain signaling may independently contribute to IBS pathophysiology in EDS. These findings highlight the importance of integrated gastrointestinal and psychological assessment in patients with EDS and support increased clinical awareness of IBS risk within this population. Future prospective studies are needed to clarify mechanistic pathways and optimize multidisciplinary management strategies for disorders of gut-brain interaction in connective tissue disease.
References
1. Yew, K.S., K.A. Kamps-Schmitt, and R. Borge, Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders. Am Fam Physician, 2021. 103(8): p. 481-492.
2. Thwaites, P.A., P.R. Gibson, and R.E. Burgell, Hypermobile Ehlers-Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know. J Gastroenterol Hepatol, 2022. 37(9): p. 1693-1709.
3. Ishiguro, H., H. Yagasaki, and Y. Horiuchi, Ehlers-Danlos Syndrome in the Field of Psychiatry: A Review. Front Psychiatry, 2021. 12: p. 803898.
4. Fakhfouri, G., N.R. Mijailović, and R. Rahimian, Psychiatric Comorbidities of Inflammatory Bowel Disease: It Is a Matter of Microglia's Gut Feeling. Cells, 2024. 13(2).
5. https://icd.who.int/browse10/2019/en.
6. https://hcup-us.ahrq.gov/db/nation/nis/nisdbdocumentation.jsp.
7. Tomarken, A.J. and N.G. Waller, Structural equation modeling: strengths, limitations, and misconceptions. Annu Rev Clin Psychol, 2005. 1: p. 31-65.
