Barrack, K. E. | bioRxiv Science

bioRxiv2024

Quantifying forms and functions of intestinal bile acid pools in mice

Bile acids (BAs) are gastrointestinal metabolites that serve dual functions in lipid absorption and cell signaling. BAs circulate actively between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with intestinal cells in vivo remain ill-defined. Through multi-site sampling of nearly 100 BA species in individual wild type mice, as well as mice lacking the ileal BA transporter, Asbt/Slc10a2, we calculate the ileal BA pool in fasting C57BL/6J mice to be [~]0.3 moles/g. Asbt-mediated transport accounts for [~]80% of this pool and amplifies size, whereas passive absorption explains the remaining [~]20%, and generates diversity. Accordingly, ileal BA pools in mice lacking Asbt are [~]5-fold smaller than in wild type controls, enriched in secondary BA species normally found in the colon, and elicit unique transcriptional responses in cultured ileal explants. This work quantitatively defines ileal BA pools in mice and reveals how BA dysmetabolism can impinge on intestinal physiology.

physiology↗

bioRxiv2023

Persistent delay in maturation of the developing gut microbiota in infants with cystic fibrosis

The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species whose prevalence and abundance reproducibly define microbiota development in early life in non-CF infants, but are missing or decreased in relative abundance in infants with CF. The consequences of these CF-specific differences in gut microbiota composition and dynamics are a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. We also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in CF, features that are associated with decreased gut bacterial density in inflammatory bowel diseases. Our results define key differences in the gut microbiota during ontogeny in CF and suggest the potential for directed therapies to overcome developmental delays in microbiota maturation.

microbiology↗