New research from scientists at St Jude Children’s Research Hospital may help reduce life-threatening respiratory problems in infants born to women who develop intrahepatic cholestasis of pregnancy (ICP), a liver disorder.
The research, which was published in Nature Communications, indicates about 30% of babies born to mothers with ICP develop respiratory distress, which proves fatal in almost 3.5% of infants, and the disorder is associated with premature delivery and stillbirth.
With a mouse model of the human disease, the researchers showed that reducing the reabsorption of bile acid in the intestines drastically improved the survival of newborn mice. The researchers modeled human ICP in mice by deleting both copies of the Abcb11 gene in female mice, and the loss led to impaired release of bile from the liver, newborn mortality, and elevated blood levels of bile, which are all characteristics of human ICP.
By using the mouse model, researchers showed that bile acid crosses the placenta. Bile acid levels were 420% higher in the offspring of female mice lacking Abcb11 when compared to the offspring of mice without the defect. The evidence suggests that the elevated blood levels leads bile acid to accumulate in the lungs of the animals.
Tests showed the lungs of mice born to mice that lacked Abcb11 developed normally, although the air sacs or alveoli did not inflate and the mice died with in 24 hours. The research team showed that at high levels, the primary bile acid elevated in human ICP disrupted the structure of surfactant, the molecule that coats and keeps alveoli inflated.
Investigators found that deleting both copies of the gene Nrli2 led to a 39% reduction in blood levels of bile acid in pregnant mice lacking Abcb11. The reduction was coupled with a 64% increase in survival of the resulting newborn mice. Deletion of Nrli2 also led to a significant reduction in three proteins involved in the reabsorption and transport of bile acids from the intestine to the liver.
“In mice, even a 30 or 40% reduction in bile acid reabsorbed in the intestines and returned to the liver resulted in survival increasing from zero to 64%,” says John Schuetz, PhD, corresponding author of the study. “The results suggest that it might be possible to develop drugs to block reabsorption of bile acid in the intestines, thus lowering bile acid concentrations in maternal blood and hopefully the risk of newborn respiratory distress as well.”
Source: Drug Discovery & Development