Li Vince W, Dong Tien S, Funes Diana, Hernandez Laura, Kushnir Nicole R, Nair Devika, Jacobs Jonathan P, Reddy Srinivasa T, Mayer Emeran A, Chang Lin, Meriwether David
Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, 90095-5347, United States.
Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1752, United States.
Mol Cell Endocrinol. 2025 Jun 1;603:112534. doi: 10.1016/j.mce.2025.112534. Epub 2025 Apr 1.
Primary estrogens and estrogen metabolites are commonly measured in human plasma and serum, but there exist almost no recent reports for human stool. This knowledge gap limits our understanding of the relationships between systemic and gut estrogens. We developed a highly sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method to determine, in human plasma and stool, the free and conjugated levels of estrone, estradiol, and estriol together with their additional hydroxyestrogen and methoxyestrogen metabolites. We investigated human stool and plasma estrogens in healthy control men; in follicular and luteal phase premenopausal women; and in postmenopausal women. Most estrogens were present in plasma and stool of all groups, while the plasma and stool levels of hydroxyestrogen and methoxyestrogen metabolites but not estrone were correlated. In stool, estrogens were higher in premenopausal women, with estrogens increasing across the menstrual cycle. We combined these LC-MS/MS measures with shotgun metagenomic sequencing of the stool microbiomes. Estrogen deconjugation enzyme gene copy numbers (β-glucuronidase and arylsulfatase) were higher in premenopausal women; while the gene copy number of β-glucuronidase + arylsulfatase, but not β-glucuronidase alone, correlated with deconjugated stool estrogens in all groups. Moreover, β-glucuronidase + arylsulfatase gene copy numbers correlated with combined plasma estrogens in men and with individual plasma estrogen metabolites in men and premenopausal women. These results support the hypothesis that gut microbial β-glucuronidase and arylsulfatase control the deconjugation of gut estrogens while modulating systemic levels through the uptake and recirculation of these deconjugated estrogens. The intestine may thus constitute an important additional compartment in estrogen physiology.
人体内的血浆和血清中通常会检测主要雌激素及其代谢产物，但关于人类粪便的最新报道几乎没有。这一知识空白限制了我们对全身雌激素与肠道雌激素之间关系的理解。我们开发了一种高灵敏度的液相色谱 - 质谱联用/质谱（LC-MS/MS）方法，用于测定人血浆和粪便中雌酮、雌二醇和雌三醇及其额外的羟基雌激素和甲氧基雌激素代谢产物的游离和结合水平。我们研究了健康对照男性、绝经前卵泡期和黄体期女性以及绝经后女性的粪便和血浆雌激素。所有组的血浆和粪便中都存在大多数雌激素，而羟基雌激素和甲氧基雌激素代谢产物（而非雌酮）的血浆和粪便水平具有相关性。在粪便中，绝经前女性的雌激素水平较高，且雌激素水平在月经周期中逐渐升高。我们将这些LC-MS/MS测量结果与粪便微生物群的鸟枪法宏基因组测序相结合。雌激素去结合酶基因拷贝数（β-葡萄糖醛酸酶和芳基硫酸酯酶）在绝经前女性中较高；而β-葡萄糖醛酸酶 + 芳基硫酸酯酶的基因拷贝数（而非单独的β-葡萄糖醛酸酶）与所有组中粪便去结合雌激素相关。此外，β-葡萄糖醛酸酶 + 芳基硫酸酯酶基因拷贝数与男性的血浆总雌激素以及男性和绝经前女性的个体血浆雌激素代谢产物相关。这些结果支持了以下假设：肠道微生物β-葡萄糖醛酸酶和芳基硫酸酯酶控制肠道雌激素的去结合，同时通过这些去结合雌激素的吸收和再循环调节全身水平。因此，肠道可能是雌激素生理学中一个重要的额外组成部分。
