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

Sulfated progesterone metabolites (PMxSs) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterized by pruritus and elevated serum bile acids. PMxSs 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). PMxSs 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, 5β-pregnan-3α,-20α-diol-3-sulfate (PM3S) and 5α-pregnan-3β-ol-20-one-sulfate (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 PMxSs increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxSs 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.NEW & NOTEWORTHY Sulfated progesterone species (PMxSs) increase postprandially in women with intrahepatic cholestasis of pregnancy (ICP) but not in women with uncomplicated pregnancy. PMxS can be enterohepatically recycled via active transport from the gut lumen by apical sodium-dependent bile acid transporter (ASBT) and stimulate gut hormone secretion. Active reabsorption of PMxS may play a role in the pruritus suffered by women with ICP. ASBT inhibition is a plausible therapy for ICP-associated pruritus.