The Microbiome Composition in Women With Recurring Intrahepatic Cholestasis of Pregnancy (ICP)

Intrahepatic Cholestasis in Pregnancy (ICP) is a disease that appears in the later stage of pregnancy with itching (pruritus) and increased risk of fetal complications. It is the most prevalent pregnancy-specific liver disease, affecting between 1 and 20 % of all pregnant women, depending on ethnicity and geographic location.

The condition is associated with an increased risk of adverse fetal outcomes, including preterm labour and intrauterine death. Further, ICP is associated with an increased risk for pre-eclampsia, thyroid disease, diabetes and cancer. ICP is typically present during the third trimester, when the serum concentrations of progesterone and estrogens reach their peak, and also, the time when the gut barrier has an increased permeability. In ICP subjects, both altered progesterone and bile acid metabolism is observed.

The underlying etiology for ICP is unknown, but there are indications that the gut microbiota may be involved. It has become increasingly clear that the gut microbiota is associated with metabolic diseases and has an important function in metabolizing endogenous and dietary metabolites. Bile acids are metabolized by the gut microbiota by deconjugation and production of secondary metabolites, ursodeoxycholic acid (UDCA) being one example of a secondary bile acid produced by the microbiota. Bile acids are produced from cholesterol by a series of hepatic enzymes generating cholic acid (CA) and chenodeoxycholic acid (CDCA) in humans that are conjugated to predominantly glycine. These primary bile acids are stored in the gall bladder from where they are released upon a meal. The majority of conjugated bile acids are reabsorbed from the ileum, but through the action of microbial bile salt hydrolase (BSH), the bile acids escape reabsorption and enter the colon where they can be further metabolized. Accordingly, bile acid deconjugation reduces enterohepatic recirculation of bile acids and thereby reduces the total bile acid pool. Reduction of bile acid levels are crucial to reduce pruritus and reduce fetal complication risks in ICP.

The aim is to identify biomarkers in the microbiota associated with ICP and the onset of this disease, or state of the disease, during pregnancy. Bacterial species that have a capability for UDCA production and correlate with sulphated progesterone metabolites are of specific interest. Furthermore, bacteria with sulphating and desulphating capabilities are also of interest.