DOI QR코드

DOI QR Code

Vascular Endothelial Growth Factor May Be Involved in the Behavioral Changes of Progeny Rats after Exposure to Ceftriaxone Sodium during Pregnancy

  • Yang, Xin (Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University) ;
  • Tang, Ting (Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University) ;
  • Li, Mengchun (Department of Pediatrics, Daping Hospital, Army Medical University) ;
  • Chen, Jie (Department of Pediatrics, Daping Hospital, Army Medical University) ;
  • Li, Tingyu (Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University) ;
  • Dai, Ying (Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University) ;
  • Cheng, Qian (Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University)
  • Received : 2021.11.30
  • Accepted : 2022.04.19
  • Published : 2022.06.28

Abstract

Antibiotic exposure during pregnancy have an adversely effects on offspring behavior and development. However, its mechanism is still poorly understood. To uncover this, we added ceftriaxone sodium to the drinking water of rats during pregnancy and conducted three-chamber sociability test, open-field test, and Morris water maze test in 3- and 6-week-old offspring. The antibiotic group offspring showed lower sociability and spatial learning and memory than control. To determine the role of the gut microbiota and their metabolites in the changes in offspring behavior, fecal samples of 6-week-old offspring rats were sequenced. The composition of dominant gut microbial taxa differed between the control and antibiotic groups. KEGG pathway analysis showed that S24-7 exerted its effects through the metabolic pathways including mineral absorption, protein digestion and absorption, Valine, leucine, and isoleucine biosynthesis. Correlation analysis showed that S24-7 abundance was negatively correlated with the level of VEGF, and metabolites associated with S24-7-including 3-aminobutanoic acid, dacarbazine, L-leucine, 3-ketosphinganine, 1-methylnicotinamide, and N-acetyl-L-glutamate-were also significantly correlated with VEGF levels. The findings suggest that antibiotic exposure during pregnancy, specifically ceftriaxone sodium, will adversely affects the behavior of offspring rats due to the imbalance of gut microbiota, especially S24-7, via VEGF and various metabolic pathways.

Keywords

Acknowledgement

We thank all the members who participated in the experiment for their help and suggestions in the whole work.

References

  1. Krischak MK, Rosett HA, Sachdeva S, Weaver KE, Robert Phillips Heine, Anna E Denoble, et al. 2020. Beyond expert opinion: a comparison of antibiotic regimens for infectious urinary tract pathology in pregnancy. AJP Rep. 10: e352-e356. https://doi.org/10.1055/s-0040-1718384
  2. Dotters-Katz S. 2020. Antibiotics for prophylaxis in the setting of preterm prelabor rupture of membranes. Obstet. Gynecol. Clin. North Am. 47: 595-603. https://doi.org/10.1016/j.ogc.2020.08.005
  3. Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, et al. 2017. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549: 528-532. https://doi.org/10.1038/nature23910
  4. Lammert CR, Frost EL, Bolte AC, Pysour MJ, Shaw ME, Bellinger CE, et al. 2018. Cutting edge: critical roles for microbiota-mediated regulation of the immune system in a prenatal immune activation model of autism. J. Immunol. 201: 845-850. https://doi.org/10.4049/jimmunol.1701755
  5. Wang X, Yang J, Zhang H, Zhang H, Yu J, Yao Z. 2019. Oral probiotic administration during pregnancy prevents autism-related behaviors in offspring induced by maternal immune activation via anti-inflammation in mice. Autism Res. 12: 576-588. https://doi.org/10.1002/aur.2079
  6. Aarts E, Ederveen THA, Naaijen J, Zwiers MP, Boekhorst J, Timmerman HM, et al. 2017.Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One 12: e0183509. https://doi.org/10.1371/journal.pone.0183509
  7. Jiang HY, Zhou YY, Zhou GL, Li Y-C. Yuan J, Li A-H, et al. 2018. Gut microbiota profiles in treatment-naive children with attention deficit hyperactivity disorder. Behav. Brain Res. 347: 408-413. https://doi.org/10.1016/j.bbr.2018.03.036
  8. Hamad AF, Alessi-Severini S, Mahmud S. Brownell M, Kuo IF. 2020. Prenatal antibiotic exposure and risk of attention-deficit/hyperactivity disorder: a population-based cohort study. CMAJ 192: E527-E535. https://doi.org/10.1503/cmaj.190883
  9. Atladottir HO, Henriksen TB, Schendel DE, Partner ET. 2012. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics 130: e1447-54. https://doi.org/10.1542/peds.2012-1107
  10. Gonzalez-Perez G, Hicks AL, Tekieli TM, Raden CM, Williams BL, Lamouse-Smith ESN. 2016. Maternal antibiotic treatment impacts development of the neonatal intestinal microbiome and antiviral immunity. J. Immunol. 196: 3768-3779. https://doi.org/10.4049/jimmunol.1502322
  11. Pingping Jiang, Alessia Trimigno, Jan Stanstrup, Bekzod Khakimov, Nanna Viereck, Soren Balling Engelsen, et al. 2017. Antibiotic treatment preventing necrotising enterocolitis alters urinary and plasma metabolomes in preterm pigs. J. Proteome Res. 16: 3547-3557. https://doi.org/10.1021/acs.jproteome.7b00263
  12. Yu M, Jia HM, Zhou C, Yang Y, Sun L-L, Zou Z-M. 2017.Urinary and fecal metabonomics study of the protective effect of Chaihu-Shu-Gan-San on antibiotic-induced gut microbiota dysbiosis in rats. Sci. Rep. 7: 46551. https://doi.org/10.1038/srep46551
  13. Ikuo Kimura, Junki Miyamoto, Ryuji Ohue-Kitano, Keita Watanabe, Takahiro Yamada, Masayoshi Onuki , et al. 2020. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science 367: eaaw8429. https://doi.org/10.1126/science.aaw8429
  14. Luo X, Zheng Y, Wen R, Deng X, Zhou L, Liao H. 2016. Effects of ceftriaxone induced intestinal dysbacteriosis on lym- phocytes in different tissues in mice. Immunobiology 221: 994-1000. https://doi.org/10.1016/j.imbio.2016.04.003
  15. Cho SW, Lee JS, Choi SH. 2004. Enhanced oral bioavailability of poorly absorbed drugs. I. Screening of absorption carrier for the ceftriaxone complex. J. Pharm. Sci. 93: 612-620. https://doi.org/10.1002/jps.10563
  16. Liu Y, Du DM, Li XF. 2010. Establishment of mice model for dysbiosis of intestinal flora. Chinese J. Microecol. 22: 293-295.
  17. Bookstaver PB, Bland CM, Griffin B, Stover KR, Eliand LS, McLaughlin M. 2015. A review of antibiotic use in pregnancy. Pharmacotherapy 35: 1052-1062. https://doi.org/10.1002/phar.1649
  18. Haas DM, Marsh DJ, Dang DT, Baker CB, Wing DA, Simhan HN, et al. 2018. Prescription and other medication use in pregnancy. Obstet. Gynecol. 131: 789-798. https://doi.org/10.1097/AOG.0000000000002579
  19. Azami M, Jaafari Z, Masoumi M, Masoumi M, Shohani M, Badfar G, et al. 2019. The etiology and prevalence of urinary tract infection and asymptomatic bacteriuria in pregnant women in Iran: a systematic review and Meta-analysis. BMC Urol. 19: 43. https://doi.org/10.1186/s12894-019-0454-8
  20. Da Silva KDL, Fernandes FEM, de Lima Pessoa T, Lima SIVC, Oliveira AG, Martins RR. 2019. Prevalence and profile of adverse drug reactions in high-risk pregnancy: a cohort study. BMC Pregnancy Childbirth 19: 199. https://doi.org/10.1186/s12884-019-2321-8
  21. Yang X, Tang T, Wen J, Li M, Chen J, Li T, et al. 2021. Effects of S24-7 on the weight of progeny rats after exposure to ceftriaxone sodium during pregnancy. BMC Microbiol. 21: 166. https://doi.org/10.1186/s12866-021-02231-0
  22. Degroote S, Hunting DJ, Baccarelli AA, Takser L. 2016. Maternal gut and fetal brain connection: increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure. Prog. Neuropsychopharmacol. Biol. Psychiatry 71: 76-82. https://doi.org/10.1016/j.pnpbp.2016.06.010
  23. Vuong HE, Pronovost GN, Williams DW, Coley EJL, Siegler EL, Qiu A, et al. 2020. The maternal microbiome modulates fetal neurodevelopment in mice. Nature 586: 281-286. https://doi.org/10.1038/s41586-020-2745-3
  24. Gao X, Jia R, Xie L, Kuang L, Feng L, Wan C. 2018. A study of the correlation between obesity and intestinal flora in school-age children. Sci. Rep. 8: 14511. https://doi.org/10.1038/s41598-018-32730-6
  25. Wexler HM. 2007. Bacteroides: the good, the bad, and the nitty-gritty. Clin. Microbiol. Rev. 20: 593-621. https://doi.org/10.1128/CMR.00008-07
  26. Buffington SA, Di Prisco GV, Auchtung TA, Ajami N, Petrosino JF, Costa-Mattioli M. 2016. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165: 1762-1775. https://doi.org/10.1016/j.cell.2016.06.001
  27. Strati F, Cavalieri D, Albanese D, De Delice C, Donati C, Hayek J, et al. 2017. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5: 24. https://doi.org/10.1186/s40168-017-0242-1
  28. Benakis C, Poon C, Lane D, Brea D, Sita G, Moore J, et al. 2020. Distinct commensal bacterial signature in the gut is associated with acute and long-term protection from ischemic stroke. Stroke 51: 1844-1854. https://doi.org/10.1161/STROKEAHA.120.029262
  29. Kim YM, Snijders AM, Brislawn CJ, Stratton KG, Zink EM, Fansler SJ, et al. 2019. Light-stress influences the composition of the murine gut microbiome, memory function, and plasma metabolome. Front. Mol. Biosci. 6: 108. https://doi.org/10.3389/fmolb.2019.00108
  30. Chen K, Fu Y, Wang Y, Liao L, Xu H, Zhang A, et al. 2020. Therapeutic effects of the in vitro cultured human gut microbiota as transplants on altering gut microbiota and improving symptoms associated with autism spectrum disorder. Microb. Ecol. 80: 475-486. https://doi.org/10.1007/s00248-020-01494-w
  31. Chen R, Wang J, Zhan R, Zhang L, Wang X. 2019. Fecal metabonomics combined with 16S rRNA gene sequencing to analyze the changes of gut microbiota in rats with kidney-yang deficiency syndrome and the intervention effect of You-gui pill. J. Ethnopharmacol. 244: 112139. https://doi.org/10.1016/j.jep.2019.112139
  32. Bourdon AK, Spano GM, Marshall W, Bellesi M, Tononi G, Serra PA, et al. 2018. Metabolomic analysis of mouse prefrontal cortex reveals upregulated analytes during wakefulness compared to sleep. Sci. Rep. 8: 11225. https://doi.org/10.1038/s41598-018-29511-6
  33. Nie C, He T, Zhang W, Zhang G. 2018. Branched chain amino acids: beyond nutrition metabolism. Int. J. Mol. Sci. 19: 954. https://doi.org/10.3390/ijms19040954
  34. Tsuneyoshi Y, Sato M, Tomonaga S, Yamane H, Morishita K, Denbow DM, et al. 2009. Oral administration of Excitin-1 (beta-alanyl-L-leucine) alters behavior and brain monoamine and amino acid concentrations in rats. Nutr. Neurosci. 12: 175-182. https://doi.org/10.1179/147683009X423346
  35. Theis V, Theiss C. 2018. VEGF - A stimulus for neuronal development and regeneration in the CNS and PNS. Curr. Protein Pept. Sci. 19: 589-597. https://doi.org/10.2174/1389203719666180104113937
  36. Sideromenos S, Lindtner C, Zambon A, Horvath O, Berger A, Pollak DD. 2020. VEGF treatment ameliorates depression-like behavior in adult offspring after maternal immune activation. Cells 9: 1048. https://doi.org/10.3390/cells9041048
  37. Yudkoff M. 2017. Interactions in the metabolism of glutamate and the branched-chain amino acids and ketoacids in the CNS. Neurochem. Res. 42: 10-18. https://doi.org/10.1007/s11064-016-2057-z
  38. Chanyachukul T, Yoovathaworn K, Thongsaard W, Chongthammakun S, Navasumrit P, Satayavivad J. 2004. Attenuation of paraquat-induced motor behavior and neurochemical disturbances by L-valine in vivo. Toxicol. Lett. 150: 259-269. https://doi.org/10.1016/j.toxlet.2004.02.007
  39. Walker AK, Wing EE, Banks WA, Dantzer R. 2019. Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Mol. Psychiatry 24: 1523-1532. https://doi.org/10.1038/s41380-018-0076-7
  40. Sanguinetti E, Collado MC, Marrachelli VG, Monleon D, Selma-Royo M, Pardo-Tendero M, et al. 2018. Microbiome-metabolome signatures in mice genetically prone to develop dementia, fed a normal or fatty diet. Sci. Rep. 8: 4907. https://doi.org/10.1038/s41598-018-23261-1
  41. Ameratunga M, Pavlakis N, Wheeler H, Grant R, Simes J, Khasraw M, et al. 2018. Anti-angiogenic therapy for high-grade glioma. Cochrane Database Syst. Rev. 11: CD008218.
  42. Griveau A, Seano G, Shelton SJ, Kupp R, Jahagiri A, Obernier K, et al. 2018. A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell 33: 874-889.e7. https://doi.org/10.1016/j.ccell.2018.03.020
  43. Zhang A, Fang H, Chen J, He L, Chen Y. 2020. Role of VEGF-A and LRG1 in abnormal angiogenesis associated with diabetic nephropathy. Front. Physiol. 11: 1064.