Profiling Bile Acids in the Stools of Humans and Animal Models of Cystic Fibrosis

Cystic fibrosis (CF) is associated with dysbiosis of the gut microbiome, alterations in intestinal mucus production, aberrant bile acid (BA) metabolism, fat malabsorption, and chronic inflammation. As little is known about BAs in CF, we performed both comprehensive and targeted BA profiling in stool of children with or without CF. Our results reveal that primary unconjugated BAs, as well as biosynthetic intermediates and atypical BAs, are elevated in children with CF (cwCF) vs. healthy controls, whereas secondary BA species and metabolites trend lower. No difference in total BA levels was found between groups. Matched bacterial metagenomic analyses showed no change in beta-diversity between groups in our small cohort, at odds with previous studies, whereas changes in relative abundance of Bacteroides (lower) and E. coli (increased) species is consistent with prior reports. In accord with CF-related shifts toward more primary and fewer secondary fecal BAs in cwCF, a robust trend was noted toward reduced abundance of bsh gene families (Wilcox test, p = 0.052) - a key rate-limiting enzyme required for bacterial synthesis of secondary BAs - in cwCF. Modest changes in both BAs and microbial BA metabolism-related gene abundances may be attributable to small sample sizes, but also suggest likely combination defects in both host and microbial BA metabolic pathways in cwCF. Importantly, fecal BA profiles from both ferret and mouse CF models failed to reflect human CF-associated BA alterations. Together, these results provide new insights into CF-related BA dysmetabolism and highlight limitations of CF animal models for BA functional studies.