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BILE SALT HYDROLASE ACTIVITY AND GUT MICROBIOME MATURATION ARE IMPAIRED IN PRETERM CHOLESTATIC INFANTS

Date
May 9, 2023
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Society: AGA

Background: Physiologic cholestasis is prevalent in preterm infants, occurring in ~15% of preterm births. Cholestasis causes poor neonatal growth and may progress to liver failure and death. Underlying causes of most cases are unknown. The potent choleretic ursodeoxycholic acid (UDCA) is used to treat cholestasis; however, its effects in preterm neonates are unclear. Microbial bile salt hydrolase (BSH) enzymes are among the numerous factors that mediate communication between the liver and the gut microbiome. BSH enzymes perform the first step in transforming primary bile salts into secondary bile salts through the deconjugation of glycine or taurine. In turn, bile salts shape gut microbiota composition and function. We sought to determine how the liver-gut-microbiome axis develops over time in preterm neonates, and whether cholestasis alters this development. Methods: We conducted a nested case-control study collecting 124 stool samples longitudinally from 24 preterm infants (mean 27.2 ± 1.8 weeks gestation), half of whom developed physiologic cholestasis. Samples were analyzed by whole metagenomic sequencing, quantitative mass spectrometry, and an in vitro BSH enzyme activity assay optimized for low microbial biomass stool samples. Results: Principal coordinate analysis revealed that gut microbiota from control preterm neonates develops over time in a predictable manner (Figure 1, P<0.0001). In control preterm neonates, acquisition of the secondary bile acid biosynthesis pathway is the most distinctive metagenomic feature of preterm microbiome development (P<0.00001). Control neonates also have increasing abundance over time of BSH genes carried by Clostridium perfringens (P<0.0001). Cholestasis interrupts this developmental pattern (P<0.05). BSH enzymatic activity is reduced in cholestatic neonates compared to controls (Figure 2, P<0.01), resulting in decreased unconjugated bile salts (46% vs 98%). Total fecal bile salt excretion was reduced in cholestasis (P<0.0001) and restored completely by enteral UDCA. However, samples from cholestatic neonates treated with UDCA had 522-fold higher quantities of fecal UDCA compared to untreated cholestatic neonates (P<0.0001), consistent with enteral UDCA being poorly absorbed in the neonatal small bowel. The majority of bile salts in early development are atypical 6-hydroxylated cholanoic acid isomers; the proportion of these isomers is reduced in cholestatic neonates (29.6% vs. 66.9%). Finally, we identified novel associations between metabolites within the BSH pathway, bile salt isomers, and neonatal growth. Conclusion: Acquisition of C. perfringens, the BSH gene, and the ability to produce secondary bile acids are key developmental features in preterm neonates that are absent in cholestasis. Metabolites within the BSH pathway warrant further study as biomarkers that may predict preterm infant growth.
<b>Figure 1</b>: Cholestasis disrupts gut microbiome maturation.

Figure 1: Cholestasis disrupts gut microbiome maturation.

<b>Figure 2</b>: Bile salt hydrolase activity is reduced in cholestatic neonates.

Figure 2: Bile salt hydrolase activity is reduced in cholestatic neonates.


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