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Maternal regulation of biliary disease in neonates via gut microbial metabolites

ABSTRACT:

Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn’s susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR) -

SUBMITTER: Li Yang

PROVIDER: MTBLS2171 | MetaboLights | 2022-01-11

REPOSITORIES: MetaboLights

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Project description:Intrahepatic cholestasis of pregnancy (ICP) is estimated to impact between 0.4% and 5% of pregnancies worldwide. This disease is associated with elevated maternal bile acids and frequently untoward neonatal outcomes such as respiratory distress and asphyxia. Multiple candidate genes have been implicated, but none have provided insight into the mechanisms of neonatal respiratory distress and death. Herein our studies demonstrate that maternal cholestasis (due to Abcb11 deficiency) produces 100% neonatal death within 24h due to atelectasis producing pulmonary hypoxia, which recapitulates the respiratory distress and asphyxia of human ICP. We show that these neonates have elevated pulmonary bile acids that are associated with disrupted structure of pulmonary surfactant. Maternal absence of Nr1i2 superimposed upon Abcb11 deficiency strongly increased neonatal survival and is directly related to reduced maternal bile acid concentrations. The mechanism accounting for reduced serum bile acids in the mothers deficient in both Nr1i2 and Abcb11 appears related to disrupted reabsorption of intestinal bile acids due to changes in transporter expression. These findings provide novel insights into pulmonary failure by revealing bile acids capability to disrupt the structure of surfactant producing collapsed alveoli, pulmonary failure and ultimately death. These findings have important implications for neonatal health especially when maternal bile acids are elevated during pregnancy and highlight a potential pathway and targets amenable to therapeutic intervention to ameliorate this condition. We used microarrays to measure changes in gene expression profiles in lung tissues from Abcb11+/- lungs after interbreeding C57BL/6 wild-type female or C57BL/6 Abcb11-/- female mice against either C57BL/6 wild-type male mice or C57BL/6 Abcb11-/- male mice to create only heterozygote offspring. We also measured profiles in liver tissues from age-matched C57BL/6 wild-type and C57BL/6 Abcb11-/- mice. Lung tissues were collected from day E17.5, E18.5 and neonatal (N0) mice. Liver tissues were collected from 1.5-month-old C57BL/6 wildtype and Abcb11-/- mice.

Project description:Biliary atresia (BA) is a rare cholestatic disease of unknown etiology that affects infants and shows an incidence of 1 out of 18,000 live births in Europe (1). The first therapeutic option is a timely performed portoenterostomy. However, the majority of patients suffer from a progressive inflammatory process, which leads to complete destruction of the extra- and intrahepatic biliary system followed by end-stage liver cirrhosis. Hence, BA is the leading indication for pediatric liver transplantation worldwide (2, 3). To understand the pathogenesis of the disease and improve theoutcome of BA patients, research has focused on the inflammatory process in liver and bile ducts, in which several factors are remarkably elevated, such as activated CD4 and CD8 T-cells, TNF alpha,IFN alpha and other proinflammatory TH1 cytokines (3-8). By the time of diagnosis, however, the disease has already reached an advanced state, characterized by the complete obstruction of the extrahepatic bile ducts with impaired bile flow and fibrosis or cirrhosis of the liver. Therefore, studies in humans focusing on the trigger mechanism of BA are limited due to the paucity of liver and availability of bile duct tissue for research. One infectious animal model has been developed, in which newborn Balb/c mice exclusively show the experimental BA phenotype after infection with rhesus rotavirus (RRV) (9, 10). This model allows the analysis of the inflammatory reactions in liver and bile ducts at early steps in the development of bile duct atresia (11-20). Furthermore, inbred mouse strains have been shown to have a different susceptibility for the development of experimental BA, suggesting that Balb/c mice have an immunological gap responsible for disease progression (10, 12). The aim of this study was to identify key genes responsible for the BA phenotype by comparing the transcriptomes at an early time point after virus infection, i.e. before bile duct atresia, between two mouse strains with different susceptibilities to BA. Differences in the virus titration and the clinical course of infected mice were analyzed, and variations in the hepatic gene response assessed by comparative microarray assays were correlated to variances in the hepatic inflammatory reaction. Balb/c mice and C57Black/6 (Black/6) mice were infected with RRV postpartum and signs of BA and survival were noted. Liver sections of diseased, healthy and control animals were assessed for T-cell expression, and the virus loads were determined. Second, mice were sacrificed after three days, and isolated hepatic RNA was subjected to gene expression analysis using Affymetrix Gene Chip MOE 430 2.0.We compared three individual expression profiles from RRV-infected Balb/c mice against 2 individual expression profiles from RRV-infected C57/BL6 control mice using the Affymetrix GeneChip MOE 430 2.0.

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Maternal regulation of biliary disease in neonates via gut microbial metabolites

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