Mucosal microbiome of CF ileum

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Defective CFTR leads to accumulation of dehydrated viscous mucus within the lumen of the intestine, luminal acidification and altered intestinal motility resulting in blockages that manifest as distal intestinal obstructive syndrome. These changes can promote gut microbial dysbiosis, adversely influencing the normal proliferation and differentiation of intestinal epithelial cells. Using Illumina 16S rRNA sequencing, we show that the ileal mucosa-associated microbiome of CFTR-null and F508del-mutant mice exhibit significant dysbiosis characterised by increased abundance of pro-inflammatory Escherichia and depletion of beneficial secondary bile-acid producing bacteria. The ileal mucosa in a human with CF was dominated by a Pseudomonas lung pathogen and absence of numerous beneficial anti-inflammatory and short chain fatty acid-producing populations. Using immunohistochemistry, we demonstrate that in both CF mice and CF human ileal tissues, there is a significant decline in the number of absorptive enterocytes, Paneth and enteroendocrine cells (EEC), notably L-type EEC that secrete gut hormones glucagon like peptide 1 and 2. In contrast, there are substantial increases in the number of stem and goblet cells. As such there is a potential role for microbiota-host interactions in the development of CF-related comorbidities.