Chenodeoxycholic Acid Improves Embryo Implantation and Metabolic Health through Modulating Gut Microbiota-Host Metabolites Interaction during Early Pregnancy.
chenodeoxycholic acid; early pregnancy; embryo implantation; gut microbiota; metabolic health; metabolites; Cell Biology; Clinical Biochemistry; Molecular Biology; Biochemistry; Physiology
Abstract :
[en] Fetus loss in early pregnancy is of major concern to both humans and animals, and this issue is largely influenced by embryo implantation. Chenodeoxycholic acid (CDCA), a primary bile acid, contributes to metabolic improvements and protects against intrahepatic cholestasis of pregnancy. However, the effect of CDCA on embryo implantation during early pregnancy has not been investigated. The present study demonstrated that CDCA administration during early pregnancy improved embryo implantation in sows and rats, thereby improving the pregnancy outcomes of sows. CDCA significantly reduced inflammation, oxidative stress, and insulin resistance. The metabolomics analysis indicated significant differences in the fecal metabolome, especially regarding the level of secondary bile acids, between the control and CDCA-treated sows. CDCA also influenced the serum metabolite profiles in sows, and the serum L-Histidine level was significantly correlated with the abundance of 19 differential fecal metabolites. Importantly, L-Histidine administration improved embryo implantation and metabolic health in rats during early pregnancy. Moreover, CDCA administration during early pregnancy also led to long-term metabolic improvements in sows. Our data indicated that CDCA improved embryo implantation by alleviating inflammation and oxidative stress, improving insulin sensitivity, and modulating the interaction between the gut microbiota and host metabolites. Therefore, CDCA intervention is a potential therapeutic strategy regarding embryo loss during pregnancy.
Disciplines :
Agriculture & agronomy
Author, co-author :
Chen, Meixia; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
Zhao, Ying ; Université de Liège - ULiège > TERRA Research Centre ; Key Laboratory of Feed Biotechnology of the Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
Ji, Haifeng; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
Li, Lu; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China ; College of Life Science and Food Engineering, Hebei University of Engineering, Handan 056038, China
Liu, Hui; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
Wang, Sixin; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
Zhang, Dongyan; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
Yin, Jingdong ; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
Wang, Jing; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
Zhang, Xin ; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
Language :
English
Title :
Chenodeoxycholic Acid Improves Embryo Implantation and Metabolic Health through Modulating Gut Microbiota-Host Metabolites Interaction during Early Pregnancy.
Bazer F.W. Wu G. Johnson G.A. Kim J. Song G. Uterine histotroph and conceptus development: Select nutrients and secreted phosphoprotein 1 affect mechanistic target of rapamycin cell signaling in ewes Biol. Reprod. 2011 85 1094 1107 10.1095/biolreprod.111.094722 21865556
Bazer F.W. Wu G. Spencer T.E. Johnson G.A. Burghardt R.C. Bayless K. Novel pathways for implantation and establishment and maintenance of pregnancy in mammals Mol. Hum. Reprod. 2010 16 135 152 10.1093/molehr/gap095 19880575
Cha J. Sun X. Dey S.K. Mechanisms of implantation: Strategies for successful pregnancy Nat. Med. 2012 18 1754 1767 10.1038/nm.3012 23223073
Wang H. Dey S.K. Roadmap to embryo implantation: Clues from mouse models Nat. Rev. Genet. 2006 7 185 199 10.1038/nrg1808 16485018
Zhang S. Lin H. Kong S. Wang S. Wang H. Wang H. Armant D.R. Physiological and molecular determinants of embryo implantation Mol. Asp. Med. 2013 34 939 980 10.1016/j.mam.2012.12.011 23290997
Agarwal A. Gupta S. Sharma R.K. Role of oxidative stress in female reproduction Reprod. Biol. Endocrinol. 2005 3 28 10.1186/1477-7827-3-28 16018814
Chen M. Li J. Zhang B. Zeng X. Zeng X. Cai S. Ye Q. Yang G. Ye C. Shang L. et al. Uterine insulin sensitivity defects induced embryo implantation loss associated with mitochondrial dysfunction-triggered oxidative stress Oxidative Med. Cell. Longev. 2021 2021 6655685 10.1155/2021/6655685
Wang F. Tian X. Zhang L. Tan D. Reiter R.J. Liu G. Melatonin promotes the in vitro development of pronuclear embryos and increases the efficiency of blastocyst implantation in murine J. Pineal. Res. 2013 55 267 274 10.1111/jpi.12069
Ochiai A. Kuroda K. Ozaki R. Ikemoto Y. Murakami K. Muter J. Matsumoto A. Itakura A. Brosens J.J. Takeda S. Resveratrol inhibits decidualization by accelerating downregulation of the CRABP2-RAR pathway in differentiating human endometrial stromal cells Cell Death Dis. 2019 10 276 10.1038/s41419-019-1511-7
Cai S. Ye Q. Zeng X. Yang G. Ye C. Chen M. Yu H. Wang Y. Wang G. Huang S. et al. CBS and MAT2A improve methionine-mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation Cell Prolif. 2021 54 e12950 10.1111/cpr.12950
Zeng X. Mao X. Huang Z. Wang F. Wu G. Qiao S. Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy Reproduction 2013 145 1 7 10.1530/REP-12-0254 23081893
Chen M. Zhang B. Cai S. Zeng X. Ye Q. Mao X. Zhang S. Zeng X. Ye C. Qiao S. Metabolic disorder of amino acids, fatty acids and purines reflects the decreases in oocyte quality and potential in sows J. Proteom. 2019 200 134 143 10.1016/j.jprot.2019.03.015 30951908
Qi X. Yun C. Pang Y. Qiao J. The impact of the gut microbiota on the reproductive and metabolic endocrine system Gut Microbes 2021 13 1894070 10.1080/19490976.2021.1894070 33722164
Priyadarshini M. Thomas A. Reisetter A.C. Scholtens D.M. Wolever T.M. Josefson J.L. Layden B.T. Maternal short-chain fatty acids are associated with metabolic parameters in mothers and newborns Transl. Res. 2014 164 153 157 10.1016/j.trsl.2014.01.012 24530607
Liu X. Li X. Xia B. Jin X. Zou Q. Zeng Z. Zhao W. Yan S. Li L. Yuan S. et al. High-fiber diet mitigates maternal obesity-induced cognitive and social dysfunction in the offspring via gut-brain axis Cell Metab. 2021 33 923 938 10.1016/j.cmet.2021.02.002 33651981
Lin T. Diao Y.F. Kang J.W. Lee J.E. Kim D.K. Jin D.I. Tauroursodeoxycholic acid improves the implantation and live-birth rates of mouse embryos Reprod. Biol. 2015 15 101 105 10.1016/j.repbio.2015.01.004
Zhang C. Gan Y. Lv J.W. Qin M.Q. Hu W.R. Liu Z.B. Ma L. Song B.D. Li J. Jiang W.Y. et al. The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice Int. Immunopharmacol. 2020 83 106442 10.1016/j.intimp.2020.106442
Broeders E.P. Nascimento E.B. Havekes B. Brans B. Roumans K.H. Tailleux A. Schaart G. Kouach M. Charton J. Deprez B. et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity Cell Metab. 2015 22 418 426 10.1016/j.cmet.2015.07.002
Teodoro J.S. Rolo A.P. Jarak I. Palmeira C.M. Carvalho R.A. The bile acid chenodeoxycholic acid directly modulates metabolic pathways in white adipose tissue in vitro: Insight into how bile acids decrease obesity NMR Biomed. 2016 29 1391 1402 10.1002/nbm.3583
Xu L. Li Y. Wei Z. Bai R. Gao G. Sun W. Jiang X. Wang J. Li X. Pi Y. Chenodeoxycholic Acid (CDCA) promoted intestinal epithelial cell proliferation by regulating cell cycle progression and mitochondrial biogenesis in IPEC-J2 cells Antioxidants 2022 11 2285 10.3390/antiox11112285
Li X. Yuan Z. Liu R. Hassan H.M. Yang H. Sun R. Zhang L. Jiang Z. UDCA and CDCA alleviate 17α-ethinylestradiol-induced cholestasis through PKA-AMPK pathways in rats Toxicol. Appl. Pharmacol. 2016 311 12 25 10.1016/j.taap.2016.10.011 27743861
Horwitz W. AOAC International. Official Methods of Analysis of AOAC 17th ed. AOAC International Arlington, VA, USA 2003
Qiu K. Qin C. Luo M. Zhang X. Sun W. Jiao N. Li D. Yin J. Protein restriction with amino acid-balanced diets shrinks circulating pool size of amino acid by decreasing expression of specific transporters in the small intestine PLoS ONE 2016 11 e0162475 10.1371/journal.pone.0162475 27611307
Wang G. Wang X. Ma Y. Cai S. Yang L. Fan Y. Zeng X. Qiao S. Lactobacillus reuteri improves the development and maturation of fecal microbiota in piglets through mother-to-infant microbe and metabolite vertical transmission Microbiome 2022 10 211 10.1186/s40168-022-01336-6 36461096
Soma-Pillay P. Nelson-Piercy C. Tolppanen H. Mebazaa A. Physiological changes in pregnancy Cardiovasc. J. Afr. 2016 27 89 94 10.5830/CVJA-2016-021 27213856
McIlvride S. Dixon P.H. Williamson C. Bile acids and gestation Mol. Asp. Med. 2017 56 90 100 10.1016/j.mam.2017.05.003 28506676
Guérin P. El Mouatassim S. Ménézo Y. Oxidative stress and protection against reactive oxygen species in the pre-implantation embryo and its surroundings Hum. Reprod. Update 2001 7 175 189 10.1093/humupd/7.2.175
Aksu K. Golal E. Aslan M.A. Ustunel I. Acar N. The investigation of the role of sirtuin-1 on embryo implantation in oxidative stress-induced mice J. Assist Reprod. Genet. 2021 38 2349 2361 10.1007/s10815-021-02229-7
Mor G. Aldo P. Alvero A.B. The unique immunological and microbial aspects of pregnancy Nat. Rev. Immunol. 2017 17 469 482 10.1038/nri.2017.64
Diedrich K. Fauser B.C. Devroey P. Griesinger G. The role of the endometrium and embryo in human implantation Hum. Reprod. Update 2007 13 365 377 10.1093/humupd/dmm011
Gnainsky Y. Granot I. Aldo P.B. Barash A. Or Y. Schechtman E. Mor G. Dekel N. Local injury of the endometrium induces an inflammatory response that promotes successful implantation Fertil. Steril. 2010 94 2030 2036 10.1016/j.fertnstert.2010.02.022
Kwak-Kim J. Bao S. Lee S.K. Kim J.W. Gilman-Sachs A. Immunological modes of pregnancy loss: Inflammation, immune effectors, and stress Am. J. Reprod. Immunol. 2014 72 129 140 10.1111/aji.12234 24661472
Kaislasuo J. Simpson S. Petersen J.F. Peng G. Aldo P. Lokkegaard E. Paidas M. Pal L. Guller S. Mor G. IL-10 to TNFα ratios throughout early first trimester can discriminate healthy pregnancies from pregnancy losses Am. J. Reprod. Immunol. 2020 83 e13195 10.1111/aji.13195 31585488
Robertson S.A. Care A.S. Moldenhauer L.M. Regulatory T cells in embryo implantation and the immune response to pregnancy J. Clin. Investig. 2018 128 4224 4235 10.1172/JCI122182 30272581
Stentz F.B. Umpierrez G.E. Cuervo R. Kitabchi A.E. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises Diabetes 2004 53 2079 2086 10.2337/diabetes.53.8.2079 15277389
He L. Guo J. Wang Y. Wang L. Xu D. Yan E. Zhang X. Yin J. Effects of dietary yeast β-glucan supplementation on meat quality, antioxidant capacity and gut microbiota of finishing pigs Antioxidants 2022 11 1340 10.3390/antiox11071340 35883831
Cao M. Li Y. Wu Q. Zhang P. Li W. Mao Z. Wu D. Jiang X. Zhuo Y. Fang Z. et al. Effects of dietary clostridium butyricum addition to sows in late gestation and lactation on reproductive performance and intestinal microbiota J. Anim. Sci. 2019 97 3426 3439 10.1093/jas/skz186
Watanabe M. Houten S.M. Mataki C. Christoffolete M.A. Kim B.W. Sato H. Messaddeq N. Harney J.W. Ezaki O. Kodama T. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation Nature 2006 439 484 489 10.1038/nature04330
Xu J. Xie S. Chi S. Zhang S. Cao J. Tan B. Protective effects of taurocholic acid on excessive hepatic lipid accumulation via regulation of bile acid metabolism in grouper Food Funct. 2022 13 3050 3062 10.1039/D1FO04085E
Nie B. Park H.M. Kazantzis M. Lin M. Henkin A. Ng S. Song S. Chen Y. Tran H. Lai R. et al. Specific bile acids inhibit hepatic fatty acid uptake in mice Hepatology 2012 56 1300 1310 10.1002/hep.25797
Teodoro J.S. Zouhar P. Flachs P. Bardova K. Janovska P. Gomes A.P. Duarte F.V. Varela A.T. Rolo A.P. Palmeira C.M. et al. Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice Int. J. Obes 2014 38 1027 1034 10.1038/ijo.2013.230 24310401
Li X. Yao X. Zhang X. Dong X. Chi S. Tan B. Zhang S. Xie S. Effects of dietary chenodeoxycholic acid supplementation in a low fishmeal diet on growth performance, lipid metabolism, autophagy and intestinal health of Pacific white shrimp, Litopenaeus vannamei Fish Shellfish Immunol. 2022 127 1088 1099 10.1016/j.fsi.2022.07.045 35872336
Geurtsen M.L. van Soest E.E.L. Voerman E. Steegers E.A.P. Jaddoe V.W.V. Gaillard R. High maternal early-pregnancy blood glucose levels are associated with altered fetal growth and increased risk of adverse birth outcomes Diabetologia 2019 62 1880 1890 10.1007/s00125-019-4957-3 31392381
Wahab R.J. Voerman E. Jansen P.W. Oei E.H.G. Steegers E.A.P. Jaddoe V.W.V. Gaillard R. Maternal glucose concentrations in early pregnancy and cardiometabolic risk factors in childhood Obesity 2020 28 985 993 10.1002/oby.22771 32320145
Yang S.L. Tan H.X. Lai Z.Z. Peng H.Y. Yang H.L. Fu Q. Wang H.Y. Li D.J. Li M.Q. An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation Cell Mol. Life Sci. 2022 79 611 10.1007/s00018-022-04639-x 36449080
Chen X. He J. Ding Y. Zeng L. Gao R. Cheng S. Liu X. Wang Y. The role of mTOR in mouse uterus during embryo implantation Reproduction 2009 138 351 356 10.1530/REP-09-0090 19443611
Wang N. Chen L. Yi K. Zhang B. Li C. Zhou X. The effects of microbiota on reproductive health: A review Crit. Rev. Food Sci. Nutr. 2022 6 1 22 10.1080/10408398.2022.2117784
Miller E.R. Ullrey D.E. The pig as a model for human nutrition Annu. Rev. Nutr. 1987 7 361 382 10.1146/annurev.nu.07.070187.002045
Cheng J.G. Rodriguez C.I. Stewart C.L. Control of uterine receptivity and embryo implantation by steroid hormone regulation of LIF production and LIF receptor activity: Towards a molecular understanding of “the window of implantation” Rev. Endocr. Metab. Disord. 2002 3 119 126 10.1023/A:1015402811650
Yoon K.T. Liu H. Zhang J. Han S. Lee S.S. Galectin-3 inhibits cardiac contractility via a tumor necrosis factor alpha-dependent mechanism in cirrhotic rats Clin. Mol. Hepatol. 2022 28 232 241 10.3350/cmh.2021.0141
Obinata H. Hla T. Sphingosine 1-phosphate and inflammation Int. Immunol. 2019 31 617 625 10.1093/intimm/dxz037 31049553
Guo L. Geng X. Ma L. Luo C. Zeng W. Ou X. Chen L. Quan S. Li H. Sphingosine-1-phosphate inhibits ceramide-induced apoptosis during murine preimplantation embryonic development Theriogenology 2013 80 206 211 10.1016/j.theriogenology.2013.04.016 23731666
Zheng X. Chen T. Jiang R. Zhao A. Wu Q. Kuang J. Sun D. Ren Z. Li M. Zhao M. et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism Cell Metab. 2021 33 791 803 10.1016/j.cmet.2020.11.017 33338411
Pi Y. Wu Y. Zhang X. Lu D. Han D. Zhao J. Zheng X. Zhang S. Ye H. Lian S. et al. Gut microbiota-derived ursodeoxycholic acid alleviates low birth weight-induced colonic inflammation by enhancing M2 macrophage polarization Microbiome 2023 11 19 10.1186/s40168-022-01458-x
Yang P. Deng F. Yuan M. Chen M. Zeng L. Ouyang Y. Chen X. Zhao B. Yang Z. Tian Z. Metabolomics reveals the defense mechanism of histidine supplementation on high-salt exposure-induced hepatic oxidative stress Life Sci. 2023 314 121355 10.1016/j.lfs.2022.121355
Feng R.N. Niu Y.C. Sun X.W. Li Q. Zhao C. Wang C. Guo F.C. Sun C.H. Li Y. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: A randomised controlled trial Diabetologia 2013 56 985 994 10.1007/s00125-013-2839-7
Rojas D.B. de Andrade R.B. Gemelli T. Oliveira L.S. Campos A.G. Dutra-Filho C.S. Wannmacher C.M. Effect of histidine administration to female rats during pregnancy and lactation on enzymes activity of phosphoryltransfer network in cerebral cortex and hippocampus of the offspring Metab. Brain Dis. 2012 27 595 603 10.1007/s11011-012-9319-5
