Wang Peng, Chen Qianqian, Yuan Peiqiang, Lin Sen, Chen Hong, Li Ran, Zhang Xiaoling, Zhuo Yong, Li Jian, Che Lianqiang, Feng Bin, Lin Yan, Xu Shengyu, Wu De, Fang Zhengfeng
Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.
College of Biological Engineering, Henan University of Technology, Zhengzhou, China.
Front Microbiol. 2022 Oct 20;13:1023623. doi: 10.3389/fmicb.2022.1023623. eCollection 2022.
Abnormally raised circulating bile acids (BA) during pregnancy threat fetal and offspring health. Our previous study has identified sulfated progesterone metabolites (PMSs) in part account for dysregulation of maternal BA homeostasis during pregnancy, however, limited intervention strategies to remedy increased serum BA through PMSs during pregnancy are available. The purpose of this study is to test the feasibility of manipulating BA homeostasis and progesterone metabolism through steering gut microbiota. A total of 19 pregnant sows were randomly treated with standard diet or vancomycin-supplemented diet, to investigate the intercorrelation of PMSs, intestinal microbiota, and maternal BA metabolism from day 60 of gestation (G60) until farrowing (L0). Pregnant mice orally gavaged with epiallopregnanolone sulfate (PM5S) or vehicle and nonpregnant mice were sampled and further analyzed to verify the effect of PM5S on maternal BA metabolism. The present study revealed that oral vancomycin reduced maternal fasting serum total BA (TBA) levels and postprandial serum TBA levels at day 90 of gestation (G90). BA profile analysis showed the decreased TBA after vancomycin treatment was attributed to the decrease of primary BA and secondary BA, especially hyodeoxycholic acid (HDCA). By using newly developed UPLC-MS/MS methods, we found vancomycin increased fecal excretion of allopregnanolone sulfate (PM4S) and PM5S during late gestation and thus maintaining the relative stability of serum PM4S and PM5S, which play an important role in BA metabolism. Further study in mice showed that pregnant mice have higher serum and liver TBA levels compared with nonpregnant mice, and PM5S administration induced higher gallbladder TBA levels and TBA pool in pregnant mice. In addition, after oral vancomycin, the continuously decreased genus, potentially enriched with genes encoding steroids sulfatase, may explain the increased fecal PMSs excretion in pregnant sows. Taken together, our study provides the evidence that pregnancy-induced elevation of BA levels in sow is likely regulated by manipulation of gut microbiota, which offer new insights into the prevention and treatment of disrupted BA homeostasis during pregnancy by targeting specific microbiota.
孕期循环胆汁酸（BA）异常升高会威胁胎儿和后代健康。我们之前的研究已确定硫酸化孕酮代谢物（PMSs）在一定程度上导致孕期母体BA稳态失调，然而，孕期通过PMSs纠正血清BA升高的干预策略有限。本研究的目的是测试通过调控肠道微生物群来操纵BA稳态和孕酮代谢的可行性。总共19头妊娠母猪被随机给予标准饮食或补充万古霉素的饮食，以研究从妊娠第60天（G60）到分娩（L0）期间PMSs、肠道微生物群和母体BA代谢的相互关系。对口服硫酸表异孕烷醇酮（PM5S）或赋形剂的妊娠小鼠以及非妊娠小鼠进行采样并进一步分析，以验证PM5S对母体BA代谢的影响。本研究表明，口服万古霉素可降低妊娠第90天（G90）时母体空腹血清总BA（TBA）水平和餐后血清TBA水平。BA谱分析显示，万古霉素治疗后TBA降低归因于初级BA和次级BA的减少，尤其是猪去氧胆酸（HDCA）。通过使用新开发的超高效液相色谱 - 串联质谱（UPLC-MS/MS）方法，我们发现万古霉素在妊娠后期增加了硫酸别孕烷醇酮（PM4S）和PM5S的粪便排泄，从而维持血清PM4S和PM5S的相对稳定性，它们在BA代谢中起重要作用。对小鼠的进一步研究表明，与非妊娠小鼠相比，妊娠小鼠的血清和肝脏TBA水平更高，并且给予PM5S会导致妊娠小鼠胆囊TBA水平和TBA池升高。此外，口服万古霉素后，持续减少的一个属，可能富含编码类固醇硫酸酯酶的基因，这可能解释了妊娠母猪粪便中PMSs排泄增加的原因。综上所述，我们的研究提供了证据表明，母猪孕期BA水平升高可能受肠道微生物群调控，这为通过靶向特定微生物群预防和治疗孕期BA稳态破坏提供了新见解。
