Distinct Gastrointestinal Symptom Phenotypes in Adults with Cystic Fibrosis are linked to complications and medication use

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ABSTRACT Background and aims Gastrointestinal symptoms remain common in adults with cystic fibrosis (CF) despite cystic fibrosis transmembrane conductance regulator modulator use, suggesting persistent and heterogeneous gut dysfunction. This prospective observational study tests the hypothesis that distinct gut symptom phenotypes in CF can be observed and linked to underlying mechanisms. Methods Adults from three UK CF centres completed the Gastrointestinal Symptom Rating Scale, Patient Assessment of Constipation Symptoms and a bowel-habit questionnaire. Latent class analysis using an ordinal logistic model was applied to 36 symptom indicators. Associations between phenotypes and demographic, clinical, and treatment variables were examined using generalised linear models. Results Three hundred participants completed questionnaires (54% male; median 31 years). We identified four symptom phenotypes: mild; moderate-constipation predominant; moderate-diarrhoea predominant and severe. The severe phenotype was associated with gastroesophageal reflux (RRR 2.86; 95%CI: 1.30-6.31; p=0.009), distal intestinal obstruction syndrome (RRR 2.46; 95%CI: 1.04-5.81; p=0.04), proton pump inhibitor (RRR 3.29; 95%CI 1.39-7.74; p=0.007), and laxative use (RRR 6.13; 95%CI 2.54-14.84; p<0.001). CF-related liver disease was associated with both moderate-constipation and diarrhoea phenotypes, respectively (RRR 2.08; 95%CI 1.13-3.81; p=0.018; RRR 2.11; 95%CI 1.03-4.29; p=0.04). There was a lower likelihood of long-term oral antibiotic use in the moderate-constipation phenotype (RRR 0.53; 95%CI 0.3-0.92; p=0.025) and moderate-diarrhoea phenotype (RRR 0.46; 95%CI 0.24-0.91; p=0.025). Conclusions Four distinct symptom phenotypes were identified, independent of demographics and pancreatic status, but associated with specific complications and medication profiles. These phenotypes provide a framework for mechanistic studies within the GRAMPUS-CF cohort and precision management of CF-related gut disease.

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