Intestinal Inflammation and Alterations in the Gut Microbiota in Cystic Fibrosis: A Review of the Current Evidence, Pathophysiology and Future Directions

Abstract

Cystic fibrosis (CF) is a life-limiting autosomal recessive multisystem disease. While its burden of morbidity and mortality is classically associated with pulmonary disease, CF also profoundly affects the gastrointestinal (GI) tract. Chronic low-grade inflammation and alterations to the gut microbiota are hallmarks of the CF intestine. The etiology of these manifestations is likely multifactorial, resulting from cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, a high-fat CF diet, and the use of antibiotics. There may also be a bidirectional pathophysiological link between intestinal inflammation and changes to the gut microbiome. Additionally, a growing body of evidence suggests that these GI manifestations may have significant clinical associations with growth and nutrition, quality of life, and respiratory function in CF. As such, the potential utility of GI therapies and long-term GI outcomes are areas of interest in CF. Further research involving microbial modulation and multi-omics techniques may reveal novel insights. This article provides an overview of the current evidence, pathophysiology, and future research and therapeutic considerations pertaining to intestinal inflammation and alterations in the gut microbiota in CF.

Faecal calprotectin and rectal histological inflammatory markers in cystic fibrosis: a single-centre study

“…Chronic intestinal inflammation is a risk factor for cancer development and this should probably be addressed early in life. 24 …”

“…Therefore, calprotectin levels detected in stools of PI patients may be higher, and this may not be exclusively attributed to intestinal inflammation 23. Perhaps, in PI PwCF, the upper limit of the considered ‘normal’ faecal calprotectin should be higher than the value considered for IBD, as no association was found with digestive symptoms 23 24. Some recent studies suggest an upper limit of >50 µg/g or 250 μg/g and it remains unclear whether reference ranges that are useful in IBD are equally applicable in CF 20 24.…”

“…Perhaps, in PI PwCF, the upper limit of the considered ‘normal’ faecal calprotectin should be higher than the value considered for IBD, as no association was found with digestive symptoms 23 24. Some recent studies suggest an upper limit of >50 µg/g or 250 μg/g and it remains unclear whether reference ranges that are useful in IBD are equally applicable in CF 20 24. Also, the pancreatic status is related to CFTR function and genotype and intestinal inflammation may be another manifestation of the multisystemic involvement of the disease and not only influenced by pancreatic function 25.…”

“…However, as the life expectancy of PwCF is increasing an increased risk of gastrointestinal malignancies has been reported. Chronic intestinal inflammation is a risk factor for cancer development and this should probably be addressed early in life 24…”

CFTR and Gastrointestinal Cancers: An Update

“…CFTR is involved in multiple physical processes in the intestine that are critical for the maintenance of tissue homeostasis, including physical barriers to protect the single cell epithelial layer, the gut microflora and management of the innate and adaptive immune responses. Disruption of these processes is associated with tissue damage, inflammation and the creation of a favorable landscape for cancer development [ 78 ]. Importantly, there is evidence of gut inflammation in both patients with CF and in CF mouse models [ 79 , 80 ].…”