Skip to main content

Advertisement

SpringerLink
Log in

Choline Supplementation During Pregnancy Protects Against Gestational Lipopolysaccharide-Induced Inflammatory Responses

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Objectives

To estimate the effects and mechanisms of choline, an essential nutrient and a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist, on the prevention of symptoms and the effects on the cholinergic anti-inflammatory pathways (CAP) in a lipopolysaccharide (LPS)-induced inflammatory response in a rat model.

Methods

Inflammation was induced by LPS treatment (1.0 µg LPS/kg body weight) on gestational day (GD) 14. Nonpregnant and pregnant Sprague Dawley rats were placed on a normal choline diet (1.1 g/kg) or supplemented choline diet (5.0 g/kg) from GDs 1 to 20. Systolic blood pressure (SBP), urinary albumin, and pregnancy outcomes were recorded. On GD 20, serum and placentas were assayed for cytokines. Western blots were used to determine the expression of placenta α7nAChR and components of the α7nAChR-CAP, including nuclear factor-κB (NF-κB) and protein kinase B (AKT). Immunohistochemistry was used to localize placental sites for the p65 subunit of NF-κB.

Results

Lipopolysaccharide significantly increased SBP and urinary albumin and decreased pregnancy outcomes, and these effects were partially reversed by higher choline treatment. Choline supplementation also significantly attenuated the LPS-induced increase in serum and placental inflammatory cytokines, decreased the expression of placental α7nAChR, lowered the activation of NF-κB signaling in placenta mononuclear cells, and inhibited placental AKT phosphorylation.

Conclusion

This study confirms that LPS induces inflammatory conditions in pregnant rats and shows that choline supplementation protects against the inflammatory symptoms through its action on α7nAChR and CAP. These observations have important implications for the prevention and treatment of inflammatory responses associated with pregnancy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Challis JR, Lockwood CJ, Myatt L, Norman JE, Strauss JF, Petraglia F. Inflammation and pregnancy. Reprod Sci. 2009;16(2):206–215.

    CAS  PubMed  Google Scholar 

  2. Szarka A, Rigó J Jr, Lazar L, Beko G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 2010;11:59.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol. 1998;179(1):80–86.

    CAS  PubMed  Google Scholar 

  4. Tosun M, Celik H, Avci B, Yavuz E, Alper T, Malatyalioglu E. Maternal and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in normal pregnancies and in pregnancies complicated by preeclampsia. J Matern Fetal Neonatal Med. 2010;23(8):880–886.

    CAS  PubMed  Google Scholar 

  5. Laham NK, Brennecke SP, Rice GE. Interleukin-8 release from human gestational tissue explants: the effects of lipopolysaccharide and cytokines. Biol Reprod. 1997;57(3):616–620.

    CAS  PubMed  Google Scholar 

  6. Munro SK, Mitchell MD, Ponnampalam AP. Histone deacetylase inhibition by trichostatin A mitigates LPS induced TNF alpha and IL-10 production in human placental explants. Placenta. 2013;34(7):567–573.

    CAS  PubMed  Google Scholar 

  7. Straley ME, Togher KL, Nolan AM, Kenny LC, O’Keeffe GW. LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation. Placenta. 2014;35(8):533–538.

    CAS  PubMed  Google Scholar 

  8. Lee J, Romero R, Xu Y, et al. A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d. PLoS One. 2011;6(2):e16806.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Shynlova O, Roderique TN, Li Y, Dorogin A, Nguyen T, Lye SJ. Infiltration of myeloid cells into decidua is a critical early event in the labour cascade and post-partum uterine remodelling. J Cell Mol Med. 2013;17(2):311–324.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Watari M, Watari H, DiSanto ME, Chacko S, Shi GP, Strauss JF. Proinflammatory cytokines induce expression of matrix-metabolizing enzymes in human cervical smooth muscle cells. Am J Pathol. 1999;154(6):1755–1762.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Buhimschi IA, Buhimschi CS, Weiner CP. Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation. Am J Obstet Gynecol. 2003;188(1):203–208.

    CAS  PubMed  Google Scholar 

  12. Yang J, Shi SQ, Shi L, Fang D, Liu H, Garfield RE. Nicotine, an alphα7 nAChR agonist, reduces lipopolysaccharide-induced inflammatory responses and protects fetuses in pregnant rats. Am J Obstet Gynecol. 2014;211(5):538.e1–7.

    PubMed  Google Scholar 

  13. Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW. A new animal model for human preeclampsia: ultra-low-dose endo-toxin infusion in pregnant rats. Am J Obstet Gynecol. 1994;171(1):158–164.

    CAS  PubMed  Google Scholar 

  14. Huang Q, Liu L, Hu B, Di X, Brennecke SP, Liu H. Decreased seizure threshold in an eclampsia-like model induced in pregnant rats with lipopolysaccharide and pentylenetetrazol treatments. PLoS One. 2014;9(2):e89333.

    PubMed  PubMed Central  Google Scholar 

  15. Bao J, Liu Y, Yang J, et al. Nicotine inhibits LPS-induced cyto-kine production and leukocyte infiltration in rat placenta. Placenta. 2016;39:77–83.

    CAS  PubMed  Google Scholar 

  16. Li X, Han X, Bao J, et al. Nicotine increases eclampsia-like seizure threshold and attenuates microglial activity in rat hippo-campus through the α7 nicotinic acetylcholine receptor. Brain Res. 2016;1642:487–496.

    CAS  PubMed  Google Scholar 

  17. Liu Y, Yang J, Bao J, et al. Activation of the cholinergic anti-inflammatory pathway by nicotine ameliorates lipopolysaccharide-induced preeclampsia-like symptoms in pregnant rats. Placenta. 2017:49:23–32.

    CAS  PubMed  Google Scholar 

  18. Zeisel SH. Choline: critical role during fetal development and dietary requirements in adults. Ann Rev Nutr. 2006;26:229–250.

    CAS  Google Scholar 

  19. Mehta AK, Singh BP, Arora N, Gaur SN. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma. Immunobiology. 2010;215(7):527–534.

    CAS  PubMed  Google Scholar 

  20. Da Costa KA, Niculescu MD, Craciunescu CN, Fischer LM, Zeisel SH. Choline deficiency increases lymphocyte apoptosis and DNA damage in humans. Am J Clin Nutr. 2006;84(1):88–94.

    PubMed  Google Scholar 

  21. Mehedint MG, Craciunescu CN, Zeisel SH. Maternal dietary choline deficiency alters angiogenesis in fetal mouse hippocampus. Proc Natl Acad Sci USA. 2010;107(29):12834–12839.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zeisel SH. The fetal origins of memory: the role of dietary choline in optimal brain development. J Pediatr. 2006;149(Suppl 5): 131–136.

    Google Scholar 

  23. Yan J, Jiang X, West AA, et al. Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans. Am J Clin Nutr. 2012;95(5):1060–1071.

    CAS  PubMed  Google Scholar 

  24. Caudill MA. Pre- and postnatal health: evidence of increased choline needs. J Am Diet Assoc. 2010;110(8):1198–1206.

    PubMed  Google Scholar 

  25. Zeisel SH, Da Costa KA, Franklin PD, et al. Choline, an essential nutrient for humans. FASEB J. 1991;5(7):2093–2098.

    CAS  PubMed  Google Scholar 

  26. Fischer LM, da Costa KA, Kwock L, Galanko J, Zeisel SH. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr. 2010;92(5):1113–1119.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fischer LM, daCosta K, Kwock L, et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr. 2007;85(5):1275–1285.

    CAS  PubMed  Google Scholar 

  28. Da Costa KA, Badea M, Fischer LM, Zeisel SH. Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts. Am J Clin Nutr. 2004;80(1):163–170.

    PubMed  Google Scholar 

  29. Buchman AL, Ament ME, Sohel M, et al. Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial. J Parenteral Enteral Nutrition. 2001;25(5):260–268.

    CAS  Google Scholar 

  30. Jiang X, Bar HY, Yan J, et al. A higher maternal choline intake among third-trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms-like tyrosine kinase-1 (sFLT1). FASEB J. 2013;27(3):1245–1253.

    CAS  PubMed  Google Scholar 

  31. Jiang X, Yan J, West AA, et al. Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans. FASEB J. 2012;26(8):3563–3574.

    CAS  PubMed  Google Scholar 

  32. Ganley OH, Graessle OE, Robinson HJ. Anti-inflammatory activity of components obtained from egg-yolk, peanut oil and soyabean lecithin. J Lab Clin Med. 1958;51(5):709–714.

    CAS  PubMed  Google Scholar 

  33. Mehta AK, Arora N, Gaur SN, Singh BP. Choline supplementation reduces oxidative stress in mouse model of allergic airway disease. Eur J Clin Invest. 2009;39(10):934–941.

    CAS  PubMed  Google Scholar 

  34. Velazquez R, Ash JA, Powers BE, et al. Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2013;58:92–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Meck WH, William CL, Cermak JM, Blusztajn JK. Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia. Front Integr Neurosci. 2007;1:1–7.

    Google Scholar 

  36. American College of Obstetricians and Gynecologists task force on hypertension in pregnancy, hypertension in pregnancy [online]. 2013:1–89. http://www.acog.org/resources_and_publications/task_force_and_work_group_reports/hypertension_in_preg nancy. Accessed May 16, 2016.

  37. Kojima H, Ito K, Tsubone H, Kuwahara M. Nicotine treatment reduces LPS-induced sickness responses in telemetry monitoring rats. J Neuroimmunol. 2011;234(1–2):55–62.

    CAS  PubMed  Google Scholar 

  38. Pavlov VA, Ochani M, Yang LH, et al. Selective alphα7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med. 2007;35(4):1139–1144.

    CAS  PubMed  Google Scholar 

  39. Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 2008;87(2):424–430.

    CAS  PubMed  Google Scholar 

  40. Hu B, Yang J, Huang Q, Bao J, Brennecke S P, Liu H. Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model. Cytokine. 2016;81:77–81.

    CAS  PubMed  Google Scholar 

  41. Pinheiro MB, Martins OA, Mota AP, et al. Severe preeclampsia goes along with a cytokine network disturbance towards a systemic inflammatory state. Cytokine. 2013;62(1):165–173.

    CAS  PubMed  Google Scholar 

  42. Tinsley JH, South S, Chiasson VL, Mitchell BM. Interleukin-10 reduces inflammation, endothelial dysfunction, and blood pressure in hypertensive pregnant rats. Am J Physiol. 2010;298(3):713–719.

    Google Scholar 

  43. Chatterjee P, Chiasson VL, Bounds KR, Mitchell BM. Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy. Front Immunol. 2014;5:1–6.

    Google Scholar 

  44. Tracey KJ. Physiology and immunology of the cholinergic anti-inflammatory pathway. J Clin Invest. 2007;117(2):289–296.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lips KS, Bruggmann D, Pfeil U, Vollerthun R, Grando SA, Kummer W. Nicotinic acetylcholine receptors in rat and human placenta. Placenta. 2005;26(10):735–746.

    CAS  PubMed  Google Scholar 

  46. Guseva MV, Hopkins DM, Scheff SW, Pauly JR. Dietary choline supplementation improves behavioral, histological, and neuro-chemical outcomes in a rat model of traumatic brain injury. J Neurotrauma. 2008;25(8):975–983.

    PubMed  PubMed Central  Google Scholar 

  47. Stevens KE, Choo KS, Stitzel JA, Marks MJ, Adams CE. Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrnα7 null mutation mice. Brain Res. 2014;1552:26–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bencherif M, Lippiello PM, Lucas R, Marrero MB. Alphα7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci. 2011;68(6):931–949.

    CAS  PubMed  Google Scholar 

  49. Sharentuya N, Tomimatsu T, Mimura K, et al. Nicotine suppresses interleukin-6 production from vascular endothelial cells: a possible therapeutic role of nicotine for preeclampsia. Reprod Sci. 2010;17(6):556–563.

    CAS  PubMed  Google Scholar 

  50. Saeed RW, Varma S, Peng-Nemeroff T, et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med. 2005;201(7):1113–1123.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen Y, Zhao M, Chen X, et al. Zinc supplementation during pregnancy through its anti-inflammatory effect. J Immunol. 2012;189(1):454–463.

    CAS  PubMed  Google Scholar 

  52. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999;401(6748):82–85.

    CAS  PubMed  Google Scholar 

  53. Yue Y, Liu R, Cheng W, et al. GTS-21 attenuates lipopolysaccharide-induced inflammatory cytokine production in vitro by modulating the Akt and NF-κB signaling pathway through the α7 nicotinic acetylcholine receptor. Int Immunopharmacol. 2015;29(2):504–512.

    CAS  PubMed  Google Scholar 

  54. Kovacheva VP, Davison JM, Mellott TJ, et al. Raising gestational choline intake alters gene expression in DMBA evoked mammary tumors and prolongs survival. FASEB J.2009;23(4):1054–1063.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics, Preterm Birth Prevention and Treatment Research Unit, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, 510623, China

    Min Zhang MD, Xinjia Han MD, PhD, Juejie Bao MS, Jinying Yang MD, Shao-Qing Shi MD, Robert E. Garfield PhD & Huishu Liu MD, PhD

Authors
  1. Min Zhang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinjia Han MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juejie Bao MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinying Yang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shao-Qing Shi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert E. Garfield PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huishu Liu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huishu Liu MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, M., Han, X., Bao, J. et al. Choline Supplementation During Pregnancy Protects Against Gestational Lipopolysaccharide-Induced Inflammatory Responses. Reprod. Sci. 25, 74–85 (2018). https://doi.org/10.1177/1933719117702247

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719117702247

Keywords

Search

Navigation