Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release.

Abstract

Sulfated progesterone metabolites (PMxS) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by pruritus and elevated serum bile acids. PMxS interact with bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1) to cause itch. We investigated whether PMxS could undergo enterohepatic recycling and stimulate intestinal GPBAR1-mediated release of gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). PMxS were quantified in pre-/postprandial serum samples (n=21) and feces (n=18) by ultra-performance liquid chromatography-tandem mass spectrometry in prospectively recruited third trimester of pregnancy outpatients with uncomplicated pregnancy or ICP. Ussing chambers were used to evaluate colonic ion secretion changes (ΔIsc) in wildtype, GPBAR1^-/-, and PYY^-/- mice by PMxS metabolites, PM3S and PM5S, and in wildtype mice with or without apical sodium bile acid transporter (ASBT) inhibition (n=6/condition). PM3S/PM5S stimulation of GLP-1 release from wildtype and GPBAR1^-/- murine crypts and human colonoids was measured by ELISA (n=3). Serum PMxS increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxS are present in feces. Apical and basolateral PM3S and PM5S stimulated PYY-mediated -ΔIsc in wildtype (p<0.01) but not GPBAR1^-/- or PYY^-/- colons. PM3S and PM5S caused GLP-1 secretion in murine crypts and human colonoids (p<0.001). ASBT inhibition blunted -ΔIsc by 68% after apical PM3S and PM5S addition (p<0.001). Serum PMxS, elevated in women with ICP and particularly postprandially, can undergo ASBT-mediated intestinal reuptake and activate GPBAR1 to stimulate gut hormone release. PMxS may therefore augment GPBAR1-mediated metabolic responses during pregnancy.