While the hallmarks of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum
disorders (HSD) are pain, joint instability, and injuries to soft tissues, most patients with hEDS and
HSD have a myriad of manifestations within the gastrointestinal tract that affect dietary tolerance
and quality of life. These include irritable bowel syndrome, functional dyspepsia, gastroparesis,
constipation, and celiac disease. Other common comorbidities include postural orthostatic tachycardia
syndrome and mast cell activation disorders, which may impact fluid and electrolyte balance, food
intolerances, and contribute to anxiety around food. Nutritional supplements are commonly used,
though research is needed to clarify their potential role in hEDS/HSD management. Patients with hEDS/
HSD benefit from the support of a multidisciplinary healthcare team. This review discusses nutritional
implications and provides practical recommendations to address the manifestations of hEDS/HSD.

Introduction

 Ehlers-Danlos syndromes (EDS) encompass a group of 14 heritable connective tissue disorders.¹ The most prevalent form of EDS is hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) with hEDS/HSD appearing to be female-predominant inherited disorders.² All types of EDS except hEDS/ HSD have identified genetic markers. HSD is also known as joint hypermobility syndrome (JHS), an older term that still appears in research. Key characteristics of hEDS/HSD are pain, fatigue, joint instability, and its consequential injuries to soft tissues.3 Patients with HSD share most of the features of hEDS, with similar symptoms, disease severity, and treatment strategies.³ Clinical features are widespread, affecting neurologic, cardiovascular, gastrointestinal, and urogynaecological systems. 

The largest prevalence study is from Wales, UK, indicating 1:500 (2%) of the general population received a formal diagnosis of hEDS or JHS.⁴ Both hEDS/HSD are currently underdiagnosed, with diagnosis typically taking 10+ years.⁵ According to an EDS worldwide survey, 97% of people with EDS report that prior to diagnosis, their healthcare team attributed their symptoms to psychological causes.⁶ Studies suggest the actual prevalence of hEDS/ HSD is closer to 3% of the general population.^4,7 

Management of hEDS/HSD involves relieving symptoms and ensuring sufficient nutrient intake. This review focuses on gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS), functional dyspepsia (FD), gastroparesis, celiac disease, and other nutrition-related disorders, such as temporomandibular joint (TMJ) dysfunction, eating disorders (EDs), autonomic disorders such as postural orthostatic tachycardia syndrome (POTS) and mast cell activation disorder (MCAD).⁸ Practical applications will be emphasized (see Table 1). 

Gastrointestinal Manifestations of hEDS/HSD 

Gastrointestinal disorders are among the most common manifestations of hEDS/HSD, with studies reporting ~90% of patients experience symptoms of diseases of gut-brain interaction (DGBIs).⁸ GI symptoms may include dysphagia, reflux, postprandial fullness, bloating, abdominal pain, nausea, vomiting, diarrhea, and constipation. Patients often attribute symptoms to eating, which can generate food fears and changes in appetite that impact nutritional intake and contribute to disordered eating patterns.⁸ 

Irritable Bowel Syndrome 

Research suggests that up to 62% of people with hEDS/HSD are diagnosed with a subtype of IBS (IBS-diarrhea, IBS-constipation, IBS-mixed, IBS-undefined).⁹ Using the ROME IV criteria, IBS is characterized by the presence of recurrent abdominal pain one day a week or more for at least 3 months and the presence of at least two symptoms related to defecation, a change in stool frequency and/or form. Visceral hypersensitivity, central sensitization, autonomic dysfunction, mast cell activation, and/or biopsychosocial factors may also contribute to symptoms of IBS. Symptomatic patients often seek nutrition guidance initially; however, organic disease must be ruled out first if there is unintentional weight loss, anemia, elevated inflammatory markers, or signs of a potential GI bleed. 

A first-line approach for IBS management is to implement the NICE (National Institutes for Health and Care Excellence) guidelines, which include:^10,11 

eating regular, small meals 

eating slowly 

hydrating adequately 

avoiding excessive caffeine, alcohol, or carbonation 

avoiding more than 3 portions of fruit or juice daily 

avoiding polyols for people with loose stools 

reducing fatty foods 

limiting insoluble high fiber foods 

Research is limited on the efficacy of the NICE guidelines; however, they are often the initial strategy because of the relative ease of implementation. 

If symptoms do not improve, a secondary approach is the low FODMAP diet (LFD) (fermentable oligo, di, monosaccharides, and polyols). The LFD involves a 2–6 week guided elimination diet of osmotically active short-chain carbohydrates, followed by a structured reintroduction phase to learn potential triggers while adding in high FODMAPs, and finally, a personalization phase to maintain intake of FODMAPs that are tolerated well.^10,11 Studies show the LFD reduces GI symptoms, such as bloating, abdominal pain, and diarrhea, in 57-82% of people with IBS.¹⁰ An LFD should only be undertaken with the guidance of a trained Registered Dietitian Nutritionist (RDN). 

In a study of 165 patients diagnosed with both IBS and JHS, and controls with IBS only, all subjects followed the LFD.¹² Patients with JHS had greater decreases in abdominal pain and bloating. The patients who had both JHS and IBS-C showed the largest improvement on an LFD compared to IBS-C controls.¹² Further studies are needed to confirm these results and understand the biological mechanism for decreased pain in patients with JHS. 

Functional Dyspepsia 

The hallmarks of functional dyspepsia (FD) include decreased appetite, postprandial distress, early satiety, nausea, belching, and epigastric pain.¹³ Studies found that between 37-86% of patients with hEDS/HSD experience FD symptoms.¹³ FD often impairs dietary intake. Limited research supports small, frequent, regular meals, eating slowly, and chewing well. There is potential benefit to limiting fatty or spicy foods, wheat, caffeine or alcohol.¹⁴ Lower adherence to the Mediterranean diet pattern has been associated with worsening of symptoms in FD, thus there may be utility to adopting the Mediterranean diet, which reduces intake of animal protein and increases intake of fruits and vegetables. Also, implementing the LFD has been shown to reduce symptoms.¹⁴ 

Gastroparesis 

Common gastroparesis symptoms include changes in appetite, nausea, vomiting, early satiety, and unintentional weight loss. A large case-control study compared hospitalized patients with and without EDS and found patients with EDS exhibited a 12.26 higher odds ratio of a concurrent diagnosis of gastroparesis.¹⁵ These results are supported by another study which found 52% of patients with GI symptoms and JHS were diagnosed with gastroparesis.¹⁶ Nutrition interventions to manage gastroparesis include smaller meals, modification of fiber intake, and post-prandial 

movement as tolerated to enhance motility. A small particle size diet, or altering food consistency by blending, processing or mashing food may help expand dietary tolerance (e.g., smoothies, mashed potatoes).¹⁷ 

Constipation 

Constipation is common; a recent study found 73% of patients with hEDS/HSD had constipation versus 16% of controls.³ The underlying etiology of constipation in hEDS/HSD is multifactorial and includes DGBIs, delayed motility, small intestinal methane overgrowth, pelvic floor dyssynergia, medication induced constipation, and rectal hyposensitivity.^8,18 Treatment should be individualized, and dietary adjustments may include eating two kiwifruit daily, gradually increasing higher fiber foods, like oats, prunes, or flaxseed, or adding soluble fiber supplements, such as psyllium husk or partially hydrolyzed guar gum.^11,19 Excess fiber intake can potentially aggravate constipation, especially without concurrent adequate water intake. Patients with comorbid rectal hyposensitivity may benefit from biofeedback, which has been studied in hEDS/ HSD.¹⁸ 

Celiac Disease 

One small study found that 16% of people with hEDS/HSD also had celiac disease.⁸ A large case control study determined the rate of celiac disease was 5.5 times higher in people with EDS than the average hospitalized patient.¹⁵ Swedish patients with EDS/JHS had an odds ratio of 2.3 of a subsequent celiac diagnosis.²⁰ A study in children with joint hypermobility (excessively lax joints, without associated pathology) found an odds ratio of 10.9% for positive celiac serology.²¹ Further studies are needed; however, celiac testing is prudent for patients with symptoms or a family history. 

People diagnosed with celiac disease need to follow a lifelong, strict gluten-free diet and benefit from consultation with an RDN. Newly diagnosed patients tend to be low in vitamins A, D, E, B12, copper, zinc, folate, and iron, and anyone following a gluten-free diet may be deficient in B vitamins, folate, iron, and calcium due to lack of enrichment and fortification of gluten-free products.²² Nutrient levels should be monitored, with diet modifications and/or supplementation as indicated. 

Other Nutrition-Related Manifestations of hEDS/HSD 

A range of conditions, including TMJ, POTS, MCAD, and EDs, are frequently found in people with hEDS/HSD. These conditions contribute to the patient’s symptom burden and add an additional layer of complexity to eating. 

Temporomandibular Joint Disorders 

While the literature is limited, 40-100% of people with EDS report headache and jaw pain.²³ A recent case-control study found that TMJ symptoms, including myofascial pain, headache, jaw pain, and disc displacement occurred more in people with hEDS than controls.²³ Dislocations or subluxations may make chewing difficult and compromise nutritional status. Pain with oral care may exacerbate dental problems. Patients with TMJ and hEDS/HSD should be referred to an RDN to ensure adequate oral intake and appropriate food consistencies, and to knowledgeable dentists and physical therapists (PTs) as needed. 

Postural Orthostatic Tachycardia Syndrome 

POTS is a form of dysautonomia affecting approximately 30% of people with hEDS/HSD.⁷ It is characterized by an increase in heart rate of 30 beats per minute (bpm) in adults (40 bpm for adolescents) in the first 10 minutes when moving from a recumbent to a standing position. Patients must have symptoms of orthostatic intolerance, such as palpitations, concentration difficulties, abnormal fatigue, presyncope, or headache for 3 or more months without another explanation.²⁴ 

Nutrition changes are the cornerstones of treatment for POTS, although medication is often needed. POTS involves hypovolemia; treatment expands blood volume via increased fluids, salt, exercise, and decreased fluid pooling with compression garments.²⁴ Over 90% of people with POTS experience GI symptoms. Most symptoms improve when sitting or recumbent; bloating, constipation and diarrhea generally do not.^7,25 People with concurrent hEDS/HSD and POTS may experience a higher burden of GI symptoms compared to those with hEDS/HSD without POTS.²⁵ 

Recommendations should be tailored based on physician guidance and co-morbid illnesses, such as cardiac diseases.^26,27 Unless contraindicated, the initial recommendations are 6 grams of salt and 2-3 liters of fluid.²⁷ Patients can gradually increase salt intake up to 10 grams, with close monitoring of symptoms, and adjustments based on clinical response.²⁴ Alcohol, caffeine, and dehydration typically worsen symptoms.²⁶ 

Two small studies investigated dietary interventions in people with POTS. In one study, 20 females with POTS (8 also had hEDS) experienced significant improvements in orthostatic and GI symptoms with a 4-week, self-reported gluten-free diet.28 Another case-control study examined 12 women with POTS who had a history of orthostatic symptoms with high glycemic foods; information on comorbid conditions such as hEDS/HSD was not provided. The study participants experienced a significant increase in tachycardia after consuming 75 grams of glucose, compared to the 13 controls.²⁹ This preliminary research suggests a gluten-free and/or a low glycemic diet deserve further study. They may be worth exploring for motivated patients who have been screened for celiac disease and are not at risk of an ED. 

Mast Cell Activation Disorders 

Mast cells (MCs) are white blood cells found in the mucosa and throughout connective tissue and skin. MC diseases include clonal diseases, which are rare and associated with genetic mutations, and non-clonal MCADs, which include mast cell activation syndrome (MCAS).³⁰ Typically, MCs respond to pathogens; however, in MCADs, MCs may respond to benign stimuli, such as temperature, food, chemicals, medications, physical exertion, stress, etc. and degranulate, causing an inflammatory cascade by releasing histamine, heparin, prostaglandins, and other mediators. MCAD symptoms affect multiple organ systems: gastrointestinal, neurologic, cardiovascular, dermatologic, and respiratory. Symptoms range from mild to anaphylaxis.³⁰ 

The only well-researched treatment for MCADs is avoidance of known MC triggers, especially in the case of anaphylaxis, and MC stabilizing medications, such as cromolyn sodium, ketotifen, or histamine blocking medications.³⁰ 

Controversy exists over diagnostic algorithms for MCADs; however, overall, studies estimate a 24-31% overlap between MCADs and hEDS.31 MCADs have potential nutritional implications, including risks for bone loss and food restriction. A low histamine diet (LHD) is commonly 

recommended, despite a lack of research.³² Aged and fermented foods are higher in histamine, but there is no universally accepted list of low histamine foods, and no experimental studies examining the clinical impact of an LHD in people with MCAD. One survey of self-reported experiences on an undefined LHD had 51.1% reporting improvement, 19.1% reporting no change and 29.8% of people who were unsure.³³ An experienced RDN should work with patients to identify patterns of foods triggering MC reactions, and advocate for the widest range of foods tolerated.³⁴ 

Eating Disorders 

Patients with GI disorders are at increased risk for developing ED and patterns of disordered eating. There is a bi-directional relationship where GI symptoms can lead to food restriction and restriction exacerbates GI symptoms. Avoidant-restrictive food intake disorder (ARFID) is an ED unrelated to weight involving fear of symptoms from eating, such as choking, pain, or nausea.³⁵ In a 2023 study, 37.9% of people with hEDS/HSD had a positive ARFID screen using the Nine Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS).36 A positive screen was associated with changing diets, skipping meals, eliminating foods, and seeking or receiving nutritional support, such as enteral feeding.³⁶ 

Patients should be screened to identify an ED, although the NIAS has not been validated for people with GI disorders.³⁷ An experienced ED specialist can discern the difference between necessary vigilance due to pain, disease management or disordered eating. A multi-disciplinary approach is necessary, including an RDN, psychological support, and medical interventions when appropriate. 

Supplement Use in hEDS/HSD 

Supplements are widely used; however, research on utility for hEDS/HSD is lacking. Supplements should be discussed with patients reporting use or expressing interest. There are currently no evidence-based recommendations for dietary supplementation to treat hEDS/HSD, nor supplements that will benefit all patients. Supplementation regimens should be based on nutrition assessments of individual patients. Research specific to hEDS/ HSD is needed, particularly on the supplements mentioned below. 

Antioxidants 

Mantle et al. proposed a 12-nutrient and antioxidant protocol intended to address various forms of EDS in 2004.³⁸ No trials have been published on this. Three studies explored supplement use, and 61- 81% of patients with hEDS/HSD report taking supplements.^36,39,40 Patients frequently reported using vitamins C, D and magnesium in all studies and B vitamins and multivitamins in two studies.^39,40 

Collagen 

Abnormal synthesis and processing of collagen proteins and the extracellular matrix (ECM) are recognized in EDS, with some of the specific proteins and genetic variants identified.⁴¹ The collagen or ECM variants associated with hEDS/ HSD have not yet been identified.² Collagen synthesis always requires adequate dietary intake of amino acids and cofactors. However, no data suggests excess collagen from any source or type provides additional benefit for hEDS/HSD. 

Folate 

A recent review postulates that hEDS/HSD might be due to a common polymorphism known as a methylenetetrahydrofolate reductase (MTHFR) deficiency that prevents the proper usage of vitamin B9, or folate. The solution would be providing the supplemental 5-methyltetrahydrofolate and/ or decreasing folic acid supplementation.⁴² The authors allude to trials of folate supplementation in patients with hEDS/HSD but did not share the number of patients, the dose used, or if they confirmed that those patients had MTHFR mutations, or the wider context of interactions with the methionine cycle. There are no published trials in patients with hEDS/HSD. Further research is warranted, and more information is needed before practice guidelines can be developed. 

CONCLUSION 

Patients with hEDS/HSD experience a wide range of manifestations that impact nutrient intake, digestion, and food tolerance and will benefit from specialized nutrition guidance and having access to resources (See Table 2). Common comorbidities, such as DGBIs, other GI disorders, EDs, MCAD, and POTS add additional layers of complexity. Each patient with hEDS/HSD will need a plan tailored to their individual circumstances. Supplement usage is common, and clinicians should query about usage and evaluate its appropriateness. Clinicians should anticipate that patients will benefit from coordinated support from a multi-disciplinary team including RDNs. 

References

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