Skip to main content
SpringerLink
Log in

Metabolomic profiling of maternal plasma identifies inverse associations of acetate and urea with anti-SARS-CoV-2 antibody titers following COVID-19 vaccination during pregnancy

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

We conducted a comprehensive metabolomic analysis of plasma samples obtained from pregnant women who displayed varying post-vaccination antibody titers after receiving mRNA-1273-SARS-CoV-2 vaccines. The study involved 62 pregnant women, all of whom had been vaccinated after reaching 24 weeks of gestation. To quantify post-vaccination plasma antibody titers, we employed binding antibody units (BAU) in accordance with the World Health Organization International Standard. Subsequently, we classified the study participants into three distinct BAU/mL categories: those with high titers (above 2000), medium titers (ranging from 1000 to 2000), and low titers (below 1000). Plasma metabolomic profiling was conducted using 1H nuclear magnetic resonance spectroscopy, and the obtained data were correlated with the categorized antibody titers. Notably, in pregnant women exhibiting elevated anti-SARS-CoV-2 antibody titers, reduced plasma concentrations of acetate and urea were observed. A significant negative correlation between these compounds and antibody titers was also evident. An analysis of metabolomics pathways revealed significant inverse associations between antibody titers and four distinct amino acid metabolic pathways: (1) biosynthesis of phenylalanine, tyrosine, and tryptophan; (2) biosynthesis of valine, leucine, and isoleucine; (3) phenylalanine metabolism; and (4) degradation of valine, leucine, and isoleucine. Additionally, an association between the synthesis and degradation pathways of ketone bodies was evident. In conclusion, we identified different metabolic pathways that underlie the diverse humoral responses triggered by COVID-19 mRNA vaccines during pregnancy. Our data hold significant implications for refining COVID-19 vaccination approaches in expectant mothers.

Key messages

  • Anti-SARS-CoV-2 antibody titers decline as the number of days since COVID-19 vaccination increases.

  • Anti-SARS-CoV-2 antibody titers are inversely associated with acetate, a microbial-derived metabolite, and urea.

  • Amino acid metabolism is significantly associated with SARS-CoV-2 antibody titers.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The dataset utilized in this study will be accessible in the supplementary information section, in accordance with the guidelines for data availability.

Abbreviations

BAU:

Binding antibody units

NMR:

Nuclear magnetic resonance

BMI:

Body mass index

Hb:

Hemoglobin

KEGG:

Kyoto Encyclopedia of Genes and Genomes

PLA-DA:

Partial least-squares discriminant analysis

References

  1. WHO reference number: WHO/2019-nCoV/FAQ/Pregnancy/Vaccines/2022.1. https://www.who.int/publications/i/item/WHO-2019-nCoV-FAQ-Pregnancy-Vaccines-2022.1. Accessed 15 Feb 2022

  2. Central Epidemic Command Center (CECC) explains details on list of individuals eligible for government-funded vaccination and those who can receive vaccination in current phase. 2021–06–22. https://www.cdc.gov.tw/En/Bulletin/Detail/I4B7jdERBn3f0TvhIeKNBA?typeid=158. Accessed 22 June 2021

  3. Fotiou M, Fotakis C, Tsakoumaki F, Athanasiadou E, Kyrkou C, Dimitropoulou A, Tsiaka T, Chatziioannou AC, Sarafidis K, Menexes G et al (2018) (1)H NMR-based metabolomics reveals the effect of maternal habitual dietary patterns on human amniotic fluid profile. Sci Rep 8:4076. https://doi.org/10.1038/s41598-018-22230-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Orczyk-Pawilowicz M, Jawien E, Deja S, Hirnle L, Zabek A, Mlynarz P (2016) Metabolomics of human amniotic fluid and maternal plasma during normal pregnancy. PLoS ONE 11:e0152740. https://doi.org/10.1371/journal.pone.0152740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sasaki E, Kusunoki H, Momose H, Furuhata K, Hosoda K, Wakamatsu K, Mizukami T, Hamaguchi I (2019) Changes of urine metabolite profiles are induced by inactivated influenza vaccine inoculations in mice. Sci Rep 9:16249. https://doi.org/10.1038/s41598-019-52686-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Diray-Arce J, Conti MG, Petrova B, Kanarek N, Angelidou A, Levy O (2020) Integrative metabolomics to identify molecular signatures of responses to vaccines and infections. Metabolites 10. https://doi.org/10.3390/metabo10120492

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ballout RA, Kong H, Sampson M, Otvos JD, Cox AL, Agbor-Enoh S, Remaley AT (2021) The NIH Lipo-COVID Study: a pilot NMR investigation of lipoprotein subfractions and other metabolites in patients with severe COVID-19. Biomedicines 9. https://doi.org/10.3390/biomedicines9091090

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bizkarguenaga M, Bruzzone C, Gil-Redondo R, SanJuan I, Martin-Ruiz I, Barriales D, Palacios A, Pasco ST, Gonzalez-Valle B, Lain A et al (2022) Uneven metabolic and lipidomic profiles in recovered COVID-19 patients as investigated by plasma NMR metabolomics. NMR Biomed 35:e4637. https://doi.org/10.1002/nbm.4637

    Article  CAS  PubMed  Google Scholar 

  9. Bruzzone C, Bizkarguenaga M, Gil-Redondo R, Diercks T, Arana E, Garcia de Vicuna A, Seco M, Bosch A, Palazon A, San Juan I et al (2020) SARS-CoV-2 infection dysregulates the metabolomic and lipidomic profiles of serum. iScience 23:101645. https://doi.org/10.1016/j.isci.2020.101645

  10. Julkunen H, Cichonska A, Slagboom PE, Wurtz P, Nightingale Health UKBI (2021) Metabolic biomarker profiling for identification of susceptibility to severe pneumonia and COVID-19 in the general population. Elife 10. https://doi.org/10.7554/eLife.63033

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kimhofer T, Lodge S, Whiley L, Gray N, Loo RL, Lawler NG, Nitschke P, Bong SH, Morrison DL, Begum S et al (2020) Integrative modeling of quantitative plasma lipoprotein, metabolic, and amino acid data reveals a multiorgan pathological signature of SARS-CoV-2 infection. J Proteome Res 19:4442–4454. https://doi.org/10.1021/acs.jproteome.0c00519

    Article  CAS  PubMed  Google Scholar 

  12. Lodge S, Nitschke P, Kimhofer T, Coudert JD, Begum S, Bong SH, Richards T, Edgar D, Raby E, Spraul M et al (2021) NMR spectroscopic windows on the systemic effects of SARS-CoV-2 infection on plasma lipoproteins and metabolites in relation to circulating cytokines. J Proteome Res 20:1382–1396. https://doi.org/10.1021/acs.jproteome.0c00876

    Article  CAS  PubMed  Google Scholar 

  13. Masuda R, Lodge S, Nitschke P, Spraul M, Schaefer H, Bong SH, Kimhofer T, Hall D, Loo RL, Bizkarguenaga M et al (2021) Integrative modeling of plasma metabolic and lipoprotein biomarkers of SARS-CoV-2 infection in Spanish and Australian COVID-19 patient cohorts. J Proteome Res 20:4139–4152. https://doi.org/10.1021/acs.jproteome.1c00458

    Article  CAS  PubMed  Google Scholar 

  14. Meoni G, Ghini V, Maggi L, Vignoli A, Mazzoni A, Salvati L, Capone M, Vanni A, Tenori L, Fontanari P et al (2021) Metabolomic/lipidomic profiling of COVID-19 and individual response to tocilizumab. PLoS Pathog 17:e1009243. https://doi.org/10.1371/journal.ppat.1009243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chiu CY, Cheng ML, Chiang MH, Wang CJ, Tsai MH, Lin G (2020) Metabolomic analysis reveals distinct profiles in the plasma and urine associated with IgE reactions in childhood asthma. J Clin Med 9. https://doi.org/10.3390/jcm9030887

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jacob D, Deborde C, Lefebvre M, Maucourt M, Moing A (2017) NMRProcFlow: a graphical and interactive tool dedicated to 1D spectra processing for NMR-based metabolomics. Metabolomics 13:36. https://doi.org/10.1007/s11306-017-1178-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Levin EG, Lustig Y, Cohen C, Fluss R, Indenbaum V, Amit S, Doolman R, Asraf K, Mendelson E, Ziv A et al (2021) Waning immune humoral response to BNT162b2 COVID-19 vaccine over 6 months. N Engl J Med 385:e84. https://doi.org/10.1056/NEJMoa2114583

    Article  CAS  PubMed  Google Scholar 

  18. Gray KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N, Baez AM, Shook LL, Cvrk D, James K et al (2021) Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol 225: 303 e301–303 e317. https://doi.org/10.1016/j.ajog.2021.03.023

  19. Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, Baum A, Pascal K, Quandt J, Maurus D et al (2020) COVID-19 vaccine BNT162b1 elicits human antibody and T(H)1 T cell responses. Nature 586:594–599. https://doi.org/10.1038/s41586-020-2814-7

    Article  CAS  PubMed  Google Scholar 

  20. Zuo L, Ao G, Wang Y, Gao M, Qi X (2022) Bamlanivimab improves hospitalization and mortality rates in patients with COVID-19: a systematic review and meta-analysis. J Infect 84:248–288. https://doi.org/10.1016/j.jinf.2021.09.003

    Article  CAS  PubMed  Google Scholar 

  21. Dispinseri S, Secchi M, Pirillo MF, Tolazzi M, Borghi M, Brigatti C, De Angelis ML, Baratella M, Bazzigaluppi E, Venturi G et al (2021) Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival. Nat Commun 12:2670. https://doi.org/10.1038/s41467-021-22958-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Earle KA, Ambrosino DM, Fiore-Gartland A, Goldblatt D, Gilbert PB, Siber GR, Dull P, Plotkin SA (2021) Evidence for antibody as a protective correlate for COVID-19 vaccines. Vaccine 39:4423–4428. https://doi.org/10.1016/j.vaccine.2021.05.063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J et al (2020) Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 11:1620. https://doi.org/10.1038/s41467-020-15562-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dagla I, Iliou A, Benaki D, Gikas E, Mikros E, Bagratuni T, Kastritis E, Dimopoulos MA, Terpos E, Tsarbopoulos A (2022) Plasma metabolomic alterations induced by COVID-19 vaccination reveal putative biomarkers reflecting the immune response. Cells 11. https://doi.org/10.3390/cells11071241

    Article  PubMed  PubMed Central  Google Scholar 

  25. He M, Huang Y, Wang Y, Liu J, Han M, Xiao Y, Zhang N, Gui H, Qiu H, Cao L et al (2022) Metabolomics-based investigation of SARS-CoV-2 vaccination (Sinovac) reveals an immune-dependent metabolite biomarker. Front Immunol 13:954801. https://doi.org/10.3389/fimmu.2022.954801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shook LL, Atyeo CG, Yonker LM, Fasano A, Gray KJ, Alter G, Edlow AG (2022) Durability of anti-spike antibodies in infants after maternal COVID-19 vaccination or natural infection. JAMA 327:1087–1089. https://doi.org/10.1001/jama.2022.1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Thomas T, Stefanoni D, Reisz JA, Nemkov T, Bertolone L, Francis RO, Hudson KE, Zimring JC, Hansen KC, Hod EA et al (2020) COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight 5. https://doi.org/10.1172/jci.insight.140327

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang Y, Yue Q, Zhu H, Song J, Li D, Liu W, Jiang S, Jiang N, Qiu C, Ai J et al (2022) Serum metabolic correlates of the antibody response in subjects receiving the inactivated COVID-19 vaccine. Vaccines (Basel) 10. https://doi.org/10.3390/vaccines10111890

    Article  PubMed  PubMed Central  Google Scholar 

  29. Knopp RH, Warth MR, Charles D, Childs M, Li JR, Mabuchi H, Van Allen MI (1986) Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biol Neonate 50:297–317. https://doi.org/10.1159/000242614

    Article  CAS  PubMed  Google Scholar 

  30. Waage CW, Mdala I, Stigum H, Jenum AK, Birkeland KI, Shakeel N, Michelsen TM, Richardsen KR, Sletner L (2022) Lipid and lipoprotein concentrations during pregnancy and associations with ethnicity. BMC Pregnancy Childbirth 22:246. https://doi.org/10.1186/s12884-022-04524-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ghini V, Maggi L, Mazzoni A, Spinicci M, Zammarchi L, Bartoloni A, Annunziato F, Turano P (2022) Serum NMR profiling reveals differential alterations in the lipoproteome induced by Pfizer-BioNTech vaccine in COVID-19 recovered subjects and naive subjects. Front Mol Biosci 9:839809. https://doi.org/10.3389/fmolb.2022.839809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nogal A, Louca P, Zhang X, Wells PM, Steves CJ, Spector TD, Falchi M, Valdes AM, Menni C (2021) Circulating levels of the short-chain fatty acid acetate mediate the effect of the gut microbiome on visceral fat. Front Microbiol 12:711359. https://doi.org/10.3389/fmicb.2021.711359

    Article  PubMed  PubMed Central  Google Scholar 

  33. Antunes KH, Stein RT, Franceschina C, da Silva EF, de Freitas DN, Silveira J, Mocellin M, Leitao L, Fachi JL, Pral LP et al (2022) Short-chain fatty acid acetate triggers antiviral response mediated by RIG-I in cells from infants with respiratory syncytial virus bronchiolitis. EBioMedicine 77:103891. https://doi.org/10.1016/j.ebiom.2022.103891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Balmer ML, Ma EH, Bantug GR, Grahlert J, Pfister S, Glatter T, Jauch A, Dimeloe S, Slack E, Dehio P et al (2016) Memory CD8(+) T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44:1312–1324. https://doi.org/10.1016/j.immuni.2016.03.016

    Article  CAS  PubMed  Google Scholar 

  35. Zhang F, Lau RI, Liu Q, Su Q, Chan FKL, Ng SC (2023) Gut microbiota in COVID-19: key microbial changes, potential mechanisms and clinical applications. Nat Rev Gastroenterol Hepatol 20:323–337. https://doi.org/10.1038/s41575-022-00698-4

    Article  CAS  PubMed  Google Scholar 

  36. Luu M, Weigand K, Wedi F, Breidenbend C, Leister H, Pautz S, Adhikary T, Visekruna A (2018) Regulation of the effector function of CD8(+) T cells by gut microbiota-derived metabolite butyrate. Sci Rep 8:14430. https://doi.org/10.1038/s41598-018-32860-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shen B, Yi X, Sun Y, Bi X, Du J, Zhang C, Quan S, Zhang F, Sun R, Qian L et al (2020) Proteomic and metabolomic characterization of COVID-19 patient sera. Cell 182(59–72):e15. https://doi.org/10.1016/j.cell.2020.05.032

    Article  CAS  Google Scholar 

  38. Zhang F, Wan Y, Zuo T, Yeoh YK, Liu Q, Zhang L, Zhan H, Lu W, Xu W, Lui GCY et al (2022) Prolonged impairment of short-chain fatty acid and L-isoleucine biosynthesis in gut microbiome in patients with COVID-19. Gastroenterology 162(548–561):e544. https://doi.org/10.1053/j.gastro.2021.10.013

    Article  CAS  Google Scholar 

  39. Neinast M, Murashige D, Arany Z (2019) Branched chain amino acids. Annu Rev Physiol 81:139–164. https://doi.org/10.1146/annurev-physiol-020518-114455

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors express their gratitude to the Metabolomics Core Laboratory housed within the Healthy Aging Research Center (HARC) at Chang Gung University and the Clinical Metabolomics Core Laboratory located at Chang Gung Memorial Hospital. The metabolomics experiments were generously supported by grant CLRPG3K0024.

Funding

This study was financially supported by the Chang Gung Medical Foundation (grant no. CORPVVL0021).

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, New Taipei Municipal Tu Cheng Hospital, New Taipei City, Taiwan

    An-Shine Chao, Kuan-Ju Chen & Chih-Wei Chien

  2. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan

    An-Shine Chao, Chiao-Yun Lin, Kuan-Ju Chen, Chih-Wei Chien, Yao-Lung Chang & Angel Chao

  3. Gynecologic Cancer Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Chiao-Yun Lin & Angel Chao

  4. Clinical Metabolomics Core Lab, Chang , Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Meng-Han Chiang, Kuan-Ying Lu, Cheng-Kun Tsai, Gigin Lin & Chih-Yung Chiu

  5. Department of Infectious Control, Chang , Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan

    Ting-Shu Wu

  6. Department of Medical Imaging and Intervention and Institute for Radiological Research, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan

    Gigin Lin

  7. Division of Pediatric Pulmonology, Department of Pediatrics, Chang , Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan

    Chih-Yung Chiu

Authors
  1. An-Shine Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiao-Yun Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng-Han Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kuan-Ying Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng-Kun Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kuan-Ju Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chih-Wei Chien
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ting-Shu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yao-Lung Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Angel Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gigin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chih-Yung Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study concept and design: ASC and CYC; manuscript writing: ASC, CYC, AC, and CYL; data analysis and interpretation: ASC, CYC, CYL, AC, MHC, KYL, CKT, KJC, CWC, TSW, YLC, and GL. All authors reviewed the manuscript.

Corresponding authors

Correspondence to An-Shine Chao or Chih-Yung Chiu.

Ethics declarations

Ethics approval

The study was approved by the local Institutional Review Board (reference no. 202101286B0).

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 670 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chao, AS., Lin, CY., Chiang, MH. et al. Metabolomic profiling of maternal plasma identifies inverse associations of acetate and urea with anti-SARS-CoV-2 antibody titers following COVID-19 vaccination during pregnancy. J Mol Med (2024). https://doi.org/10.1007/s00109-024-02438-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00109-024-02438-4

Keywords

Search

Navigation