Understanding Gut Symptoms in People With Cystic Fibrosis

Although chest infections affect wellbeing and survival in cystic fibrosis (CF), most people with CF also have difficulty digesting food and must take medication for this. In spite of this treatment, two thirds of people with CF miss school or work because of tummy symptoms (pain, bloating and wind). In some cases these symptoms become severe leading to bowel obstruction and hospital admission. Long term, people with CF have a greater risk of bowel cancer. The investigators asked people with CF and health professionals to suggest the most important questions for research. Treatment of gut symptoms was in their top 10 list. Current treatments are often ineffective because the investigators do not fully understand why symptoms occur. GRAMPUS-CF SRC will describe accurately the categories of gut symptoms in CF and find out why they occur. The investigators will do this using magnetic resonance imaging (MRI) scans and tests which give a detailed description of the germs in the bowel or which measure inflammation. The investigators will also study the effects of diet, using a questionnaire. The investigators will link these results together, using advanced statistics to find the factors causing gut symptoms. The investigators will then identify treatments which are likely to be helpful. In future work the investigators will test these in clinical trials.

This is a multicentre longitudinal observational study Study.

Hypothesis 1 - Distinct phenotypes of gut symptoms in CF can be defined, using symptom questionnaires.

Hypothesis 2 - These phenotypes will be characterised by differences in mechanism, elucidated by MRI physiology, gut microbiome, inflammatory markers and dietary factors.

Hypothesis 3 - Integration of mechanistic data will identify pathways which can be targeted by new and repurposed therapeutics, dietary modifications and biomarkers to identify those patients likely to benefit.

Study Design Tiered study (3 groups), using latent class analysis to characterise phenotypes of CF gut symptoms, from clinical and questionnaire data.

No control group. The investigators will conduct a longitudinal study comprising nested groups A to C of the study population, with progressively more detailed mechanistic investigations.

Group A will complete a CF-specific measure of gut symptoms (CFAbd-Score) and a generic constipation scoring using the 'Patient Assessment of Constipation-Symptoms' (PAC-SYM) and a dietary questionnaire (Intake24). Participants will provide questionnaire data at 3 time points, 6 months apart (baseline, 6 and 12 months).

Group B will have stool and blood for microbiome, inflammatory mediators and faecal fat. Participants will provide stool and blood samples at 3 time points, 6 months apart (baseline, 6 and 12 months).

Group C will have gut MRI and exploratory studies of inflammation (immune gene expression and micro RNA analysis). Participants will spend approximately 6 hours in the MRI scanning suite on a single day.

Group A - 300 adults \& 50 children. Group B - 100 adults \& 20 children (group B participants will be drawn from group A).

Group C - 40 adults \& 10 children (group C participants will be drawn from group B).

Total final enrolment 300 adults \& 50 children

Eligibility Criteria:
Inclusion Criteria:

1. Confirmed diagnosis of cystic fibrosis (clinical features of CF combined with either a genotype known to be associated with CF or a diagnostic sweat chloride).
2. For participants enrolled in group A via the mobile phone app, self-reported diagnosis will be accepted.
3. Adult patients will be aged 16 years and over and attend the Nottingham or Leeds CF Centres.
4. Paediatric patients will be aged 6-15 years and attend the Nottingham CF Centre.
5. Capacity to consent, or to understand the requirements of the study where parent or guardian consent is needed.
6. English-speaking (the panel of questionnaires the investigators will use has so far been validated only in English).

Exclusion Criteria:

EXCLUSIONS TO PARTICIPATION IN ANY PART OF THE STUDY

1. Self-reported diagnosis of an additional gastrointestinal condition e.g. inflammatory bowel disease, coeliac disease or gastrointestinal cancer.
2. Patients from Leeds previously enrolled in the IGLOO-CF Study\* \* Data from the IGLOO-CF Study will form the validation dataset for the latent class analysis in GRAMPUS-CF.

EXCLUSIONS TO PARTICIPATION IN GROUP C (MRI SCANS)

1. Measurement of Forced Expiratory Volume in 1 second (FEV1) of \<40% predicted using Global Lung Initiative criteria, according to clinical records.
2. Contra-indication to MRI scanning, such as embedded metal, pacemaker.
3. Unable to stop medications directly prescribed to alter bowel habit, such as laxatives of anti-diarrhoeals, on the study day.
4. Previous resection of any part of the gastro-intestinal tract apart from appendicectomy or cholecystectomy. Surgical relief of distal intestinal obstruction syndrome or neonatal ileus will be permitted unless clinical records show excision of intestine \>20cm in length.
5. Intestinal stoma
6. Diagnosis of inflammatory bowel disease or coeliac disease confirmed by biopsy
7. Gastrointestinal malignancy
8. Unable to comply with dietary restrictions required for the study
9. Pregnancy - tests are available at the Sir Peter Mansfield Imaging Centre if participants are unsure.