Genetic Carbohydrate Maldigestion As Model to Study Food Hypersensitivity Mechanism (WORK PACKAGE 2) (GenMalCarb2)

Genetic Carbohydrate Maldigestion As a Model to Study Food Hypersensitivity Mechanism and Guide Personalised Treatment Using a Non-invasive Multiparametric Test (WORK PACKAGE 2)

Irritable bowel syndrome (IBS) affects one in seven people with gastrointestinal (GI) symptoms that are detected without an established underlying organic cause. 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). The development of therapeutic options is hampered by the heterogeneity of IBS, the lack of specificity of its symptom-based definitions, and the poor understanding of the underlying pathophysiological mechanisms.

Many people with IBS find that certain foods (particularly carbohydrates) trigger their symptoms and avoiding such foods has been shown to be effective in IBS. An example of such a diet is the low-FODMAP (fermentable oligo-, di-, monosaccharides and polyols) exclusion diet, developed by researchers at Monash University. This has suggested that the food-symptom relation may involve malabsorption of carbohydrates due to inefficient enzymatic breakdown of polysaccharides. However, only a percentage of subjects respond to this diet. Overall, the current findings relating to SI, suggest a strong potential for effective personalized therapeutic (dietary) interventions in subgroups of IBS subjects and suggest similar mechanisms should be investigated in relation to other genes involved in the digestion and absorption of carbohydrates (CDGs). This project aims to understand what the mechanisms for GI symptoms in subjects with these genetic alterations are. Aim of the study is to assess the gut response to a sucrose challenge in single-and double-carriers of the common hypomorphic sucrase-isomaltase variant p. (Val15Phe) vs non- carriers (negative controls) and CSID subjects (positive controls), applying an MRI multiparametric test combined with a breath test.

Study Overview

• Status: Not yet recruiting
• Conditions: Sucrase Isomaltase Deficiency
• Intervention / Treatment: Other: Blood, stool and saliva collection; Other: Questionnaire completion; Diagnostic test: Magnetic Resonance Imaging (MRI) and Breath test

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

• Study Contact: Name: Maura Corsetti, Medical Doctor; Phone Number: +447976448821; Email: maura.corsetti@nottingham.ac.uk

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG7 2UH
    • University of Nottingham
    • Contact: Maura Corsetti, Medical Doctor; Phone Number: 0044 7976448821; Email: maura.corsetti@nottingham.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Single-centre study. CSID subjects will be identified and recruited either with the help of the PPI group through advertisements on social media or flyers at Clinical Genetics and Genomic Conferences and Adult Metabolic Disorder Conferences.

Healthy participants will be recruited through social media advertisements and posters.

Description

Inclusion Criteria for CSID subjects:

• Aged ≥18 (all groups)
• Subjects with genetically proven CSID
• Previous negative endoscopy with biopsies excluding IBD or microscopic colitis in people above 50 years old.
• Negative relevant additional screening (including exclusion of coeliac disease with TTG and IgA)
• Ability to conform to the study protocol including the sucrose challenge.

Exclusion Criteria for CSID subjects:

• Subjects on opioids and use of drugs known to alter GI motility for the duration of the study.
• Presence of concurrent organic gastrointestinal disease (inflammatory bowel disease, coeliac disease, cancer), or a major disease such as diabetes, uncontrolled thyroid disease
• Any history of bowel surgery (not appendectomy or cholecystectomy)
• Contraindication to MRI scanning
• Having taken part in another interventional research study within 3 months
• Concurrent major confounding condition (e.g. alcohol or substance abuse in the last 2 years) based on the study clinician's judgement.

Inclusion Criteria for healthy participants:

• Aged ≥18 years
• Absence of Rome III IBS criteria
• Non-SI variant confirmed (group 1) or Single-SI variants confirmed (group 2) or Double - SI variants confirmed (group 3)
• Ability to conform to the study protocol including the sucrose challenge

Exclusion Criteria for healthy participants:

• 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).
• Any history of bowel surgery (not appendectomy or cholecystectomy)
• Contraindication to MRI scanning
• Having taken part in another interventional research study within 3 months
• Concurrent major confounding condition (e.g. alcohol or substance abuse in the last 2 years) based on the clinician's judgement.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Congenital Sucrase-Isomaltase Deficiency; Subjects with congenital sucrase-isomaltase deficiency (CSID) who report symptoms	Other: Blood, stool and saliva collection; Blood, stool and saliva collection; Other: Questionnaire completion; Questionnaire on: Hospital Anxiety and Depression Score (HADS) 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; Patient Health Questionnaire 12 (PHQ-12) Somatic Symptom scale; Diagnostic test: Magnetic Resonance Imaging (MRI) and Breath test; MRI scans and breath test samples collected after drink test with sucrose
Healthy subjects; Subjects without CSID	Other: Blood, stool and saliva collection; Blood, stool and saliva collection; Other: Questionnaire completion; Questionnaire on: Hospital Anxiety and Depression Score (HADS) 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; Patient Health Questionnaire 12 (PHQ-12) Somatic Symptom scale; Diagnostic test: Magnetic Resonance Imaging (MRI) and Breath test; MRI scans and breath test samples collected after drink test with sucrose
Asymptomatic controls single carriers; Subjects single carriers for sucrose isomaltase deficiency without symptoms	Other: Blood, stool and saliva collection; Blood, stool and saliva collection; Other: Questionnaire completion; Questionnaire on: Hospital Anxiety and Depression Score (HADS) 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; Patient Health Questionnaire 12 (PHQ-12) Somatic Symptom scale; Diagnostic test: Magnetic Resonance Imaging (MRI) and Breath test; MRI scans and breath test samples collected after drink test with sucrose
Asymptomatic controls double carriers; Subjects double carriers for sucrose isomaltase deficiency without symptoms	Other: Blood, stool and saliva collection; Blood, stool and saliva collection; Other: Questionnaire completion; Questionnaire on: Hospital Anxiety and Depression Score (HADS) 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; Patient Health Questionnaire 12 (PHQ-12) Somatic Symptom scale; Diagnostic test: Magnetic Resonance Imaging (MRI) and Breath test; MRI scans and breath test samples collected after drink test with sucrose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve	Area under curve (AUC) of the change from baseline for the MRI measured small bowel water content after the drink test with sucrose	0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Habitual diet questionnaire	subject will report food eaten at each meal	during 4 days before the MRI study
MRI measured colon free water content	MRI measured colon free water content, (in arbitrary units) after the drink test	0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test
MRI measured small bowel and colon gas content	small bowel and colon gas content (in arbitrary units) after the drink test	0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test
MRI measured small bowel and colon volume	small bowel and colon volume in arbritary units after drink test	0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test
MRI measured oro-caecal transit time	oro-caecal transit time (OCTT), (in arbitrary units) after the drink test	0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test
Breath hydrogen and methane concentration measured in parts per million after drink test		baseline and then 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test
Symptoms of nausea, gas/flatulence, bloating and pain/discomfort measured using a Composite Symptom Score after the drink test		0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test
Total glucose and fructose and excess fructose, lactose, sorbitol, mannitol, oligosaccharides (Fructans and GOS) as measured by Comprehensive Nutrition Assessment Questionnaire	CNAQ questionnaires results	time 0
Hospital Anxiety and Depression Score	scale measuring the score of anxiety and depression	time 0
The Patient Health Questionnaire 12	Scale measuring the psychosomatic score	Time 0
Stool microbiota taxonomic	Analysis of of microbiota taxonomic in the two stool samples collected by patient during the day before the MRI study day	Up to 3 days before the MRI study
Stool microbiota alpha and beta diversity measurements	Analysis of alfa and beta diversity of microbiota in the two stool samples collected by patient before the study day	Up to three days before the MRI study day
Serum levels of short chain fatty acids	Serum levels	At baseline and 0, 60, 120, 180, 240, 300 minutes after the drink test
Circulating blood glucose levels		Baseline and then 0, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, 300 minutes after the drink test
Serum levels of surrogates of intestinal permeability (occludin, lipopolysaccharide binding protein)	Serum levels	At baseline and 0, 60, 120, 180, 240, 300 minutes after the drink test
Serum levels of lipidome and free fatty acids	Serum levels	At baseline and 0, 60, 120, 180, 240, 300 minutes after the drink test
Serum levels of total serum N-glycome and glucose	Serum levels	At baseline and 0, 60, 120, 180, 240, 300 minutes after the drink test
Food and drink avoidance questionnaire	patients will respond to the below questions: Name of the food or drink you try to avoid.; Please tell us if you try to avoid this food or drink partially or completely? Approximately how long you have tried to avoid this food or drink partially or completely. Why do you try to avoid this food or drink partially or completely (including if you have been told to avoid it by a health care professional such as a doctor or dietitian)	at time 0
Leeds Food Preference Questionnaire	The LFPQ consists of two tasks requiring different interaction from the participant. One task requires an explicit evaluation of each food item using visual analogue scales. The other requires a quick choice to be made between paired combinations of foods. The order of task completion is randomised.	at time 0
Food Craving Questionnaire - State (FCQ-S)	participants respond to 14 questions about sugary food and they will respond with a scale from 1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree, 5 = strongly agree.	at time 0

Collaborators and Investigators

• Sponsor: University of Nottingham
• Collaborators: Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel; cic bioGune; University of Veterinary Medicine Hannover
• Investigators: Principal Investigator: Maura Corsetti, Medical Doctor, University of Nottingham

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: November 21, 2024
• First Submitted That Met QC Criteria: January 7, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 7, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: sucrose isomaltase deficiency
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Food Hypersensitivity
• Other Study ID Numbers: FMHS 215-0624

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No