GenMalCarb: Genetic Carbohydrate Maldigestion as a Model to Study Food Hypersensitivity

Sponsor

Nottingham University Hospitals NHS Trust (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05795049

Collaborator

CICbioGUNE (Other), Christian-Albrechts-University of Kiel (Other), University of Veterinary Medicine Hannover (Other)

2,000

Enrollment

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Irritable bowel syndrome (IBS) affects one in seven people with gastrointestinal (GI) symptoms. IBS strongly impacts quality of life, is a leading cause of work absenteeism, and consumes 0.5% of the healthcare annual budget. It manifests in women more than men with symptoms including abdominal pain, bloating, constipation (IBS-C), diarrhoea (IBS-D), and mixed presentations (IBS-M) (1). The development of therapeutic options is hampered by the poor understanding of the underlying cause of symptoms.

Many patients find that certain foods (particularly carbohydrates) trigger their symptoms, and avoiding such foods has been shown effective in IBS, like in the low-FODMAP (fermentable oligo-, di-, mono-saccharides and polyols) exclusion diet.

This has suggested that the food-symptom relation may involve malabsorption of carbohydrates due to inefficient digestion. However only a percentage of patients respond to this diet. Recently it has been reported that a subset of IBS carries hypomorphic (defective) gene variant of the sucrase isomaltase (SI), the enzyme that normally digests carbohydrates, sucrose and starch. This carbohydrate maldigestion (the breakdown of complex carbohydrates by a person's small bowel enzymes) is characterized by diarrhoea, abdominal pain and bloating, which are also features of IBS. This possibly occurs via accumulation of undigested carbohydrates in the large bowel, where they cause symptoms due to gas production following bacterial fermentation. Similar mechanisms may be acting at the level of other enzymes involved in the digestion, breakdown and absorption of carbohydrates (carb digestion genes -CDGs). Aim of the study is to study the prevalence of this genetic alteration in a large number of IBS patients as compared to asymptomatic controls.

Condition or Disease	Intervention/Treatment	Phase
Irritable Bowel Syndrome (IBS) Sucrase Isomaltase Deficiency	Other: Stool and saliva sample collection Other: Questionnaire completion

Study Design

Study Type:

Observational

Anticipated Enrollment :

2000 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Genetic Carbohydrate Maldigestion as a Model to Study Food Hypersensitivity Mechanism and Guide Personalised Treatment Using a Non-invasive Multiparametric Test (Work Package 1)

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Apr 30, 2025

Anticipated Study Completion Date :

Apr 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
IBS Patient IBS patient with diarrhoea or alternating bowel habit	Other: Stool and saliva sample collection Stool and saliva samples collection Other: Questionnaire completion Questionnaire on; demographic, ethnicity, IBS subtype, post-infection onset, previous surgeries IBS severity score for adults Hospital Anxiety and Depression scores for adults Somatization score for adults Total glucose and fructose and excess fructose, lactose, sorbitol, mannitol, oligosaccharides (Fructans and GOS) as measured by CNAQ questionnaire for adults and children Quality of Life as measured by the PedsQL™ GI Symptoms Module GI symptoms as measured by the PedsQL™ GI Symptoms Module Anxiety, Depression as measured by the Pediatric PROMIS®
Healthy subject Participants without IBS	Other: Stool and saliva sample collection Stool and saliva samples collection Other: Questionnaire completion Questionnaire on; demographic, ethnicity, IBS subtype, post-infection onset, previous surgeries IBS severity score for adults Hospital Anxiety and Depression scores for adults Somatization score for adults Total glucose and fructose and excess fructose, lactose, sorbitol, mannitol, oligosaccharides (Fructans and GOS) as measured by CNAQ questionnaire for adults and children Quality of Life as measured by the PedsQL™ GI Symptoms Module GI symptoms as measured by the PedsQL™ GI Symptoms Module Anxiety, Depression as measured by the Pediatric PROMIS®

Arm

Intervention/Treatment

IBS Patient

IBS patient with diarrhoea or alternating bowel habit

Other: Stool and saliva sample collection

Stool and saliva samples collection

Other: Questionnaire completion

Questionnaire on; demographic, ethnicity, IBS subtype, post-infection onset, previous surgeries IBS severity score for adults Hospital Anxiety and Depression scores for adults Somatization score for adults Total glucose and fructose and excess fructose, lactose, sorbitol, mannitol, oligosaccharides (Fructans and GOS) as measured by CNAQ questionnaire for adults and children Quality of Life as measured by the PedsQL™ GI Symptoms Module GI symptoms as measured by the PedsQL™ GI Symptoms Module Anxiety, Depression as measured by the Pediatric PROMIS®

Healthy subject

Participants without IBS

Other: Stool and saliva sample collection

Stool and saliva samples collection

Other: Questionnaire completion

Outcome Measures

Primary Outcome Measures

number of IBS-D and IBS-M with of SI and CDG hypomorphic variants as compared to asymptomatic controls [baseline]
the prevalence of SI and CDG hypomorphic variants in IBS-D and IBS-M patients across countries and ethnicities, compared to asymptomatic controls

Secondary Outcome Measures

Difference in age between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - age in years
Difference in gender between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - gender
Difference in ethnicity between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - ethnicity
Difference in IBS subtype between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - number of patients with IBS with diarrhoea (IBS-D) and with mixed bowel habit (IBS-M)
Difference in post-infectious onset between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - number of patients with post-infectious onset
Difference in number of previous abdominal surgery between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - number of patients with IBS with previous abdominal surgery
Difference in symptoms presentations between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - IBS symptoms severity score for adults. This score range between 0 and 500 and a change of at least 50 is considered a clinically relevant change.
Difference in anxiety and depression between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - Hospital Anxiety and Depression score for adults. A score up to 7 for anxiety and or depression is considered Normal; between 8-10 Borderline abnormal (borderline case) and between 11-21 = Abnormal (case)
Difference in somatisation between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - Somatization score for adults. a score of 5, 10, and 15 represent cutpoints for low, medium, and high somatic symptom severity, respectively.
Difference in habitual intake of sugars between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - Total glucose and fructose and excess fructose, lactose, sorbitol, mannitol, oligosaccharides (Fructans and GOS) as measured by CNAQ questionnaire for adults and children
Difference in quality of life between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - Quality of Life as measured by the Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms (PedsQL™ GI Symptoms) Scale. The high.er the PedsQL score, the better the quality of life
Difference in symptoms between patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - GI symptoms using those reported in the Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Module
Difference in anxiety and depression between paediatric patients carriers and non-carriers of defective (hypomorphic) gene [baseline]
Evaluate whether the below parameters differs between patients carriers and non-carriers of defective (hypomorphic) gene: - Anxiety, Depression as measured by the Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS®). This use a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population. A score of 60 is one SD higher than the mean of the reference population.
Difference in in vitro SI enzyme activity in human cells with defective gene as compare with those with normal gene [baseline]
Difference in the intensity of the SI protein bands of immunoprecipitations of monoclonal anti-SI antibodies that recognize different conformations of the SI protein

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria for Patients:

Patients age between 5 and 70 years of age.
Patients with IBS-D or IBS-M as defined by the Rome III criteria.
Previous negative endoscopy with biopsies excluding IBD or microscopic colitis in patients above 50 years old
Negative relevant additional screening or consultation whenever appropriate
Ability to conform to the study protocol

Exclusion Criteria for Patients:

Patients with IBS-C or IBS-U according to Rome III criteria
Patients with any condition which, in the opinion of the investigator, makes the patient unsuitable for participation in the study.
Patients on opioids
Patients with concurrent organic gastrointestinal disease (inflammatory bowel disease, celiac disease, cancer), or a major disease such as diabetes, uncontrolled thyroid disease
Patients with a history of bowel surgery (not appendectomy or cholecystectomy)
Concurrent major confounding condition, e.g. alcohol or substance abuse in the last 2 years (clinician's judgement).

Inclusion Criteria for healthy controls:

Between 5 and 70 years of age
Absence of Rome III IBS criteria

Exclusion Criteria for healthy controls:

Blood relatives of the participating IBS patient are not allowed to participate.
Person with any condition which, in the opinion of the investigator, makes them unsuitable for participation in the study.
Person presenting with a functional or organic GI disorder.
Person presenting with underlying disease that may involve the GI tract (e.g. Parkinson's disease) or be associated with GI symptoms (e.g. anorexia nervosa, major depression).