DISCUSSION
This is the first study investigating associations between gastrointestinal (GI) symptoms -assessed by the Dutch GI Symptom Tracker-, anxiety/depression and health-related quality of life (HRQoL) in Dutch pwCF.
Elevated levels of GI symptoms and anxiety/depression were prevalent in pwCF. As hypothesized, more GI symptoms were associated with more symptoms of anxiety, depression and worse HRQoL. In our data, ‘Eating Challenges’ and ‘Stools’ had the highest/worst scores, highlighting the severity of these symptoms; both scales were significantly, positively associated with elevated anxiety, depression and worse HRQoL. In general, this study provided strong evidence of convergent and divergent validity, finding statistically significant relationships between GI symptoms and related domains of HRQoL, but no relationship to CFQ-R Respiratory Symptoms.
Recent studies have recognized the synergies between psychological symptoms, specifically depression, and changes in inflammation in the gut microbiota.12 Our results suggest new targets for treatment (depression) that may reduce inflammation in the gut and improve HRQoL in pwCF and vice versa: targeting gut symptoms might reduce anxiety/depression and improve HRQoL. The treatment of CF has been transformed by the development of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as elexacaftor/ tezacaftor/ivacaftor.34 For many patients, this has led to improvements in lung function, respiratory symptoms, and sweat chloride concentrations.35However, the impact of modulators on GI symptoms is relatively unknown.7, 36 Several studies on gastrointestinal patient-reported outcome measures (GI-PROMs) in relation to epithelial transport inhibitors (ETIs) and CFTR-modulators in CF have shown promising results, including improved intestinal function, hepatobiliary complications and decreased episodes of GI inflammation, illustrated by decreased fecal calprotectin levels. 37,38 Although quality of life may improve for many who started modulator treatment,39 a variety of negative side effects with potential impacts on safety and well‐being have been reported, including neuropsychiatric changes.40 In our study sample, the majority (68.2 % of adults and 90% of adolescents) used modulators. Large epidemiologic studies are needed to better characterize these relationships.
Strengths and limitations should be considered. This is an innovative pilot study with clinical implications regarding assessing and treating GI symptoms. This study was limited by a relatively small sample size, especially of adolescents. A larger sample size would increase the statistical power of our analyses and improve their generalizability. However, even with this relatively small sample and an adjustment for multiple testing by using a significance cut-off value <0.001, the predicted relationships between GI symptoms and mental health and quality of life were found to be statistically significant.
Another limitation is that some participants completed the measures online whereas others completed them in clinic; differences in mode of administration may have led to response biases. Finally, there is a possibility of ascertainment bias, given that individuals with fewer symptoms or lower socioeconomic status may have been less inclined to share their screening outcomes for research purposes.
Moreover, additional studies are needed to identify and address factors that might influence GI symptoms, anxiety/depression and HRQoL in pwCF. In a future study, we plan to investigate the gut microbiome and the influence of dietary intake to gain insights into their relationship to GI symptoms. Another future study should examine the complex interplay between GI symptoms, systemic inflammatory markers and mood disorders in CF, given that these systems seemed to be linked in the gut-brain-axis.12
Studying the relationship between these systemic inflammatory markers, GI symptoms and mood disorders can provide insight in the underlying mechanisms, identify biomarkers for disease activity and treatment response, and develop targeted therapeutic interventions. A clear relationship between gut and brain has been described in other diseases, like inflammatory bowel disease and functional gastrointestinal disorders,41, 42 but data on CF and gut-brain-axis is yet limited.