PROJECT SUMMARY/ABSTRACT
Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) are prevalent but
underdiagnosed conditions associated with excess morbidity. Despite improved recognition, many patients are
still misdiagnosed with chronic fatigue syndrome, fibromyalgia, psychosomatic and functional GI disorders etc.
There is now ample data linking hEDS/HSD with `functional' GI symptoms and disordered autonomic nervous
system (ANS) control. However, little is known about the pathophysiology that connects these disabling
comorbidities. A complete lack of targeted treatment options naturally follows the paucity of mechanistic data.
A dysregulated ANS response circuit is closely linked to enhanced GI visceral hypersensitivity. This bio-
evolutionary model of the ANS is described in the Polyvagal Theory (Porges 1995) and aligns well with the
aberrant brain-gut axis concept of functional disorders of gut-brain interaction (DGBIs). This hyperreactivity to
bodily perturbations, controlled by brainstem nuclei that regulate organ function, can be non-invasively
measured via validated indices of cardiac vagal tone (vagal efficiency and respiratory sinus arrhythmia). Using
these measures, we have recently documented a poor vagal tone in adolescents with HSD. No studies have
yet explained how cardiac inhibitory signals may be dysregulated in hEDS/HSD patients with apparent
`functional' digestive symptoms.
There is paucity of data on the role of inflammation in hEDS/HSD with DGBIs. Our preliminary data from
dermal fibroblasts in hEDS demonstrate abnormal TGF-ß signaling, an important cytokine regulator. Further,
the frequent meal-related symptoms may signal an underlying gastric motor disturbance not captured by
current tests. Multimodal assessment of gastric physiology (contractility, accommodation, emptying and blood
flow in response to meal) can now be assessed with a novel gastric MRI protocol. Simultaneous pre- and post-
meal ANS function testing may further delineate brain-gut axis alterations. This feasibility study will investigate
the brain-gut-immune axis along with transcriptome studies to detect variants predisposing to tissue and blood
vessel laxity in adolescents with hEDS/HSD and functional GI complaints. We will investigate ANS function
measures (Aim 1), cytokine profiling and RNASeq of duodenal fibroblasts (Aim 2), as well as dynamic gastric
MRI (Aim 3) in a small cohort of females compared to healthy controls. The proposed studies provide an
integrative model for a common, multi-system disorder that may underlie a subset of DGBIs. Data from this
study may address an important scientific knowledge gap that crosses multiple medical disciplines.
