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

TY - JOUR

T1 - Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release

AU - Mitchell, Alice L

AU - Tough, Iain R

AU - Fan, Hei Man

AU - Lovgren-Sandblom, Anita

AU - Ovadia, Caroline

AU - Chambers, Jenny

AU - Fonseca Pedro, Patricia

AU - Tsakmaki, Anastasia

AU - Bewick, Gavin A.

AU - Marschall, Hanns-Ulrich

AU - Cox, Helen M.

AU - Williamson, Catherine

N1 - Publisher Copyright: Copyright © 2025 The Authors.

PY - 2025/4

Y1 - 2025/4

N2 - 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.

AB - 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.

KW - enterohepatic recycling

KW - gut hormones

KW - intrahepatic cholestasis of pregnancy

KW - prandial

KW - progesterone sulfate metabolites

UR - http://www.scopus.com/inward/record.url?scp=86000666077&partnerID=8YFLogxK

U2 - 10.1152/ajpgi.00211.2024

DO - 10.1152/ajpgi.00211.2024

M3 - Article

C2 - 39888313

SN - 1522-1547

VL - 328

SP - G377-G385

JO - American journal of physiology. Gastrointestinal and liver physiology

JF - American journal of physiology. Gastrointestinal and liver physiology

IS - 4

ER -