Profiling bile acids in the stools of humans and animal models of cystic fibrosis.

Cystic fibrosis (CF) is associated with aberrant bile acid (BA) metabolism. As little is known about BA in children with CF (cwCF), we performed both comprehensive (n = 89) and focused (n = 21) BA profiling in stool of children with or without CF. Our results reveal select BA species and metabolites are significantly different between cwCF and nonCF controls. Focused BA profiling revealed a significant increase in total BA levels and selected changes in a subset of BA classes for cwCF. Matched bacterial metagenomic analyses showed no change in alpha-diversity between groups in this small cohort, at odds with previous studies, whereas changes in relative abundance of Bacteroidetes (lower in cwCF) phylum are consistent with prior reports. A trend was noted toward reduced abundance of bsh gene families, a key rate-limiting enzyme required for bacterial synthesis of secondary BAs, in cwCF. Observed modest changes in both BAs and microbial BA metabolism-related gene abundances may suggest a possible combination of defects in host and microbial BA metabolic pathways in cwCF. Fecal BA profiles from both ferret and mouse CF models showed significant differences from human BA profiles, and while the ferret model reproduced significant differences between CF and nonCF animals, the nonCF animals showed higher levels of BA (opposite of what is observed in humans), indicating that neither model recapitulated BA in stool in the context of CF. Together, these results provide new insights into CF-related BA dysmetabolism in cwCF and highlight limitations of CF animal models for BA functional studies.

Importance: Changes in the abundance and/or composition of intestinal BAs may contribute to dysbiosis and altered gastrointestinal physiology in CF. Here, we report shifts in select fecal BA classes and species for cwCF. Matched metagenomic analysis suggests possible defects in both host intestinal BA absorption and gut microbial BA metabolism. Additional analyses of mouse and ferret CF stool for BA composition suggest great care must be taken when interpreting BA functional studies using these animal models. Together, this work lays technical and conceptual foundations for interrogating BA-microbe interactions in cwCF.