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Published on: August 23, 2022
Cholestasis impairs gut microbiota development and bile salt hydrolase activity in preterm neonates
Lauren E Lynch1, Amy B Hair2, Krishnakant G Soni1
1Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Insights
In preterm infants, impaired bile flow (cholestasis) disrupts the gut microbiome
Area of Science:
- Microbiology
- Neonatal Physiology
- Metabolomics
Background:
- Cholestasis in neonates impairs bile flow, leading to poor growth and potential liver failure.
- A healthy liver-gut-microbiome axis is crucial for bile acid metabolism, involving microbial transformation of primary bile acids.
- Ursodeoxycholic acid (UDCA) is used to treat neonatal cholestasis, but its interactions with gut microbes and bile acids are unclear.
Purpose of the Study:
- To investigate the development of the liver-gut-microbiome axis in extremely preterm infants.
- To understand how cholestasis affects this axis and the role of microbial bile acid deconjugation.
- To explore the impact of UDCA on bile acid profiles in cholestatic neonates.
Main Methods:
- Nested case-control study of 24 extremely preterm infants with longitudinal stool sample collection.
- Whole metagenomic sequencing to analyze microbial composition and functional genes.
- In vitro bile salt hydrolase (BSH) enzyme activity assays and quantitative mass spectrometry for bile acid metabolome analysis.
Main Results:
- Early microbiome development in preterm infants is characterized by the acquisition of secondary bile acid pathways and BSH genes from Clostridium perfringens.
- Cholestasis significantly reduces BSH gene abundance and activity, leading to lower unconjugated bile acid levels.
- UDCA treatment increases fecal UDCA levels 522-fold but does not fully restore normal bile acid profiles; isomeric bile acids are prevalent and linked to growth.
Conclusions:
- Bile acid deconjugation by gut microbes is a critical function acquired during early neonatal development.
- Cholestasis impairs this essential microbial function, impacting bile acid metabolism and potentially neonatal growth.
- Further research is needed to understand the complex interplay of bile acids, microbes, and host factors in neonatal cholestasis.
Abstract:
Cholestasis refers to impaired bile flow from the liver to the intestine. In neonates, cholestasis causes poor growth and may progress to liver failure and death. Normal bile flow requires an intact liver-gut-microbiome axis, whereby liver-derived primary bile acids are transformed into secondary bile acids. Microbial bile salt hydrolase (BSH) enzymes are responsible for the first step, deconjugating glycine- and taurine-conjugated primary bile acids. Cholestatic neonates often are treated with the potent choleretic bile acid ursodeoxycholic acid (UDCA), although interactions between UDCA, gut microbes, and other bile acids are poorly understood. To gain insight into how the liver-gut-microbiome axis develops in extreme prematurity and how cholestasis alters this maturation, we conducted a nested case-control study collecting 124 stool samples longitudinally from 24 preterm infants born at mean 27.2 ± 1.8 weeks gestation and 946 ± 249.6 g, half of whom developed physiologic cholestasis. Samples were analyzed by whole metagenomic sequencing, in vitro BSH enzyme activity assays optimized for low biomass fecal samples, and quantitative mass spectrometry to measure the bile acid metabolome. In extremely preterm neonates, acquisition of the secondary bile acid biosynthesis pathway and BSH genes carried by Clostridium perfringens are the most prominent features of early microbiome development. Cholestasis interrupts this developmental pattern. BSH gene abundance and enzyme activity are profoundly reduced in cholestatic neonates, resulting in decreased quantities of unconjugated bile acids. UDCA restores total fecal bile acid levels in cholestatic neonates, but this is due to a 522-fold increase in fecal UDCA. A majority of bile acids in early development are atypical positional and stereo-isomers of bile acids. We report novel associations linking isomeric bile acids and BSH activity to neonatal growth trajectories. These data highlight deconjugation of bile acids as a key microbial function that is acquired in early neonatal development and impaired by cholestasis.
