Gut microbiota mediates cognitive impairment in young mice after multiple neonatal exposures to sevoflurane

Meiyu Liu, Shaoyong Song, Qingcai Chen, Jianhong Sun, Wei Chu, Yunzeng Zhang, Fuhai Ji, Meiyu Liu, Shaoyong Song, Qingcai Chen, Jianhong Sun, Wei Chu, Yunzeng Zhang, Fuhai Ji

Abstract

Multiple exposures to anesthesia may increase the risk of cognitive impairment in young children. However, the mechanisms underlying this neurodevelopmental disorder remain elusive. In this study, we investigated alteration of the gut microbiota after multiple neonatal exposures to the anesthetic sevoflurane and the potential role of microbiota alteration on cognitive impairment using a young mice model. Multiple neonatal sevoflurane exposures resulted in obvious cognitive impairment symptoms and altered gut microbiota composition. Fecal transplantation experiments confirmed that alteration of the microbiota was responsible for the cognitive disorders in young mice. Microbiota profiling analysis identified microbial taxa that showed consistent differential abundance before and after fecal microbiota transplantation. Several of the differentially abundant taxa are associated with memory and/or health of the host, such as species of Streptococcus, Lachnospiraceae, and Pseudoflavonifractor. The results reveal that abnormal composition of the gut microbiota is a risk factor for cognitive impairment in young mice after multiple neonatal exposures to sevoflurane and provide insight into a potential therapeutic strategy for sevoflurane-related neurotoxicity.

Keywords: anesthesia; cognitive impairment; gut microbiota; sevoflurane.

Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Morris water maze test for control and sevoflurane-treated mice. (A) Experimental schedule: 3% sevoflurane was applied for 2 h daily on PND 6, 8, and 10, MWM test on PND 31–36, and fecal sample collection for 16S ribosomal RNA gene sequencing and fecal bacteria transplant on PND 37. (B) Body weight (Student’s t-test, p > 0.05). (C) Trace plot of control and sevoflurane-treated mice in the MWM test. (D) Escape latency (two-way ANOVA; Time: F4,72 = 67.43, p < 0.001; Group: F1,18 = 43.14, p < 0.001; Interaction: F4,72 = 3.857, p = 0.007). (E) Platform-crossing instances (Student’s t-test, p = 0.0021). (F) Time spent in the fourth quadrant (Student’s t-test, p = 0.0092). (G) Mean distance from the platform (Student’s t-test, p = 0.0041). PND: postnatal day; ANOVA: analysis of variance; MWM: Morris water maze. Data are shown as mean ± SEM (n = 10). Significance: * p < 0.05, ** p < 0.01, *** p < 0.001, ns: non-significant.
Figure 2
Figure 2
Differential abundance of gut bacteria between control (n = 5) and anesthesia (n = 4) mice. (A) Species PAC001381_s. (B) Species PAC001069_s. (C) Species PAC002302_s. (D) Species PAC002490_s. (E) Species PAC001786_s. (F) Genus Streptococcus. Taxa were assigned based on the PKSSU4.0 database implemented in the EzBioCloud platform.
Figure 3
Figure 3
Effects of transplantation of fecal microbiota from control and sevoflurane-treated mice on behavior of pseudo germ-free mice. (A) Experimental summary: fecal microbiota transplantation effects on behavioral testing in pseudo germ-free mice. Wild-type male mice were first treated by administering high doses of antibiotic solution for 14 consecutive days on PND 21–34. Thereafter, mice were orally treated with fetal microbiota of control and anesthesia mice on PND 35–48. The MWM test was performed on PND 49–54. Fecal samples were collected for 16S ribosomal RNA gene sequencing testing on PND 55. (B) Body weight (two-way ANOVA; Time: F2,72 = 959.6, p < 0.001; Group: F3,36 = 1.795, p = 0.17; Interaction: F6,72 = 1.209, p = 0.31). (C) Trace plot of mice in the MWM test. (D) Escape latency (two-way ANOVA; Time: F4,144 = 35.46, p < 0.001; Group: F3,36 = 14.51, p < 0.001; Interaction: F12,144 = 4.436, p < 0.001). (E) Platform-crossing instances (one-way ANOVA; F3,36 = 12.20, p < 0.001). (F) Time spent in the fourth quadrant (one-way ANOVA; F3,36 = 8.812, p = 0.0002). (G) Mean distance from the platform (one-way ANOVA; F3,36 = 12.56, p < 0.001). PND: postnatal day; ANOVA: analysis of variance; MWM: Morris water maze. Data are shown as mean ± SEM (n = 10). * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 4
Figure 4
Effects of fecal microbiota transplantation from anesthesia-treated (FMTS, n = 14) and control (FMTC, n = 13) mice on the composition of the host gut microbiota of pseudo-germ-free mice. (A) Species PAC001381_s. (B) Species PAC001069_s. (C) Species PAC002302_s. (D) Species PAC002490_s. (E) Species PAC001786_s. (F) Genus Streptococcus. Taxa were assigned based on the PKSSU4.0 database implemented in the EzBioCloud platform.

References

    1. Davidson A, Vutskits L. The new FDA drug safety communication on the use of general anesthetics in young children: what should we make of it? Paediatr Anaesth. 2017; 27:336–37. 10.1111/pan.13122
    1. Shi Y, Hu D, Rodgers EL, Katusic SK, Gleich SJ, Hanson AC, Schroeder DR, Flick RP, Warner DO. Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort. Paediatr Anaesth. 2018; 28:513–19. 10.1111/pan.13359
    1. Vinson AE, Houck CS. Neurotoxicity of Anesthesia in Children: Prevention and Treatment. Curr Treat Options Neurol. 2018; 20:51. 10.1007/s11940-018-0536-z
    1. Oba S, Işıl CT, Türk HŞ, Karamürsel S, Aksu S, Kaba M, Kılınç L, Dokucu AI. Evaluation of Neurotoxicity of Multiple Anesthesia in Children Using Visual Evoked Potentials. Sisli Etfal Hastan Tip Bul. 2019; 53:284–89. 10.14744/SEMB.2018.59454
    1. Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, et al.. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA. 2016; 315:2312–20. 10.1001/jama.2016.6967
    1. Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, Stargatt R, Bellinger DC, Schuster T, Arnup SJ, Hardy P, Hunt RW, Takagi MJ, et al., and GAS Consortium. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016; 387:239–50. 10.1016/S0140-6736(15)00608-X
    1. Warner DO, Zaccariello MJ, Katusic SK, Schroeder DR, Hanson AC, Schulte PJ, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Hu D, Voigt RG, Paule MG, et al.. Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology. 2018; 129:89–105. 10.1097/ALN.0000000000002232
    1. Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and Brain Structure Following Early Childhood Surgery With Anesthesia. Pediatrics. 2015; 136:e1–12. 10.1542/peds.2014-3526
    1. Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci. 2016; 17:705–17. 10.1038/nrn.2016.128
    1. Glatz P, Sandin RH, Pedersen NL, Bonamy AK, Eriksson LI, Granath F. Association of Anesthesia and Surgery During Childhood With Long-term Academic Performance. JAMA Pediatr. 2017; 171:e163470. 10.1001/jamapediatrics.2016.3470
    1. Gibert S, Sabourdin N, Louvet N, Moutard ML, Piat V, Guye ML, Rigouzzo A, Constant I. Epileptogenic effect of sevoflurane: determination of the minimal alveolar concentration of sevoflurane associated with major epileptoid signs in children. Anesthesiology. 2012; 117:1253–61. 10.1097/ALN.0b013e318273e272
    1. Edwards DA, Shah HP, Cao W, Gravenstein N, Seubert CN, Martynyuk AE. Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain. Anesthesiology. 2010; 112:567–75. 10.1097/ALN.0b013e3181cf9138
    1. Lu H, Liufu N, Dong Y, Xu G, Zhang Y, Shu L, Soriano SG, Zheng H, Yu B, Xie Z. Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice. Anesthesiology. 2017; 127:961–75. 10.1097/ALN.0000000000001889
    1. Yang Y, Zhong Z, Wang B, Xia X, Yao W, Huang L, Wang Y, Ding W. Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila. Neuropsychopharmacology. 2019; 44:2054–64. 10.1038/s41386-019-0437-1
    1. Ji MH, Wang ZY, Sun XR, Tang H, Zhang H, Jia M, Qiu LL, Zhang GF, Peng YG, Yang JJ. Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment. Mol Neurobiol. 2017; 54:3759–70. 10.1007/s12035-016-9943-x
    1. Xue L, Zou X, Yang XQ, Peng F, Yu DK, Du JR. Chronic periodontitis induces microbiota-gut-brain axis disorders and cognitive impairment in mice. Exp Neurol. 2020; 326:113176. 10.1016/j.expneurol.2020.113176
    1. Liu G, Zhu T, Zhang A, Li F, Qian W, Qian B. Heightened stress response and cognitive impairment after repeated neonatal sevoflurane exposures might be linked to excessive GABAAR-mediated depolarization. J Anesth. 2016; 30:834–41. 10.1007/s00540-016-2215-0
    1. Zheng H, Dong Y, Xu Z, Crosby G, Culley DJ, Zhang Y, Xie Z. Sevoflurane anesthesia in pregnant mice induces neurotoxicity in fetal and offspring mice. Anesthesiology. 2013; 118:516–26. 10.1097/ALN.0b013e3182834d5d
    1. Amrock LG, Starner ML, Murphy KL, Baxter MG. Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. Anesthesiology. 2015; 122:87–95. 10.1097/ALN.0000000000000477
    1. Hofacer RD, Deng M, Ward CG, Joseph B, Hughes EA, Jiang C, Danzer SC, Loepke AW. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol. 2013; 73:695–704. 10.1002/ana.23892
    1. Culley DJ, Cotran EK, Karlsson E, Palanisamy A, Boyd JD, Xie Z, Crosby G. Isoflurane affects the cytoskeleton but not survival, proliferation, or synaptogenic properties of rat astrocytes in vitro. Br J Anaesth. 2013. (Suppl 1); 110:i19–28. 10.1093/bja/aet169
    1. O’Toole PW, Jeffery IB. Gut microbiota and aging. Science. 2015; 350:1214–15. 10.1126/science.aac8469
    1. Quigley EM. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases. Curr Neurol Neurosci Rep. 2017; 17:94. 10.1007/s11910-017-0802-6
    1. Selkrig J, Wong P, Zhang X, Pettersson S. Metabolic tinkering by the gut microbiome: Implications for brain development and function. Gut Microbes. 2014; 5:369–80. 10.4161/gmic.28681
    1. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015; 28:203–09.
    1. Cryan JF, O’Riordan KJ, Cowan CS, Sandhu KV, Bastiaanssen TF, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, et al.. The Microbiota-Gut-Brain Axis. Physiol Rev. 2019; 99:1877–2013. 10.1152/physrev.00018.2018
    1. Bullich C, Keshavarzian A, Garssen J, Kraneveld A, Perez-Pardo P. Gut Vibes in Parkinson’s Disease: The Microbiota-Gut-Brain Axis. Mov Disord Clin Pract. 2019; 6:639–51. 10.1002/mdc3.12840
    1. Benakis C, Martin-Gallausiaux C, Trezzi JP, Melton P, Liesz A, Wilmes P. The microbiome-gut-brain axis in acute and chronic brain diseases. Curr Opin Neurobiol. 2020; 61:1–9. 10.1016/j.conb.2019.11.009
    1. Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC. Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation. Clin Ther. 2015; 37:984–95. 10.1016/j.clinthera.2015.04.002
    1. Obrenovich M, Jaworski H, Tadimalla T, Mistry A, Sykes L, Perry G, Bonomo RA. The Role of the Microbiota-Gut-Brain Axis and Antibiotics in ALS and Neurodegenerative Diseases. Microorganisms. 2020; 8:784. 10.3390/microorganisms8050784
    1. Serbanescu MA, Mathena RP, Xu J, Santiago-Rodriguez T, Hartsell TL, Cano RJ, Mintz CD. General Anesthesia Alters the Diversity and Composition of the Intestinal Microbiota in Mice. Anesth Analg. 2019; 129:e126–29. 10.1213/ANE.0000000000003938
    1. Li N, Wang Q, Wang Y, Sun A, Lin Y, Jin Y, Li X. Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis. Stress. 2019; 22:592–602. 10.1080/10253890.2019.1617267
    1. Ganci M, Suleyman E, Butt H, Ball M. The role of the brain-gut-microbiota axis in psychology: The importance of considering gut microbiota in the development, perpetuation, and treatment of psychological disorders. Brain Behav. 2019; 9:e01408. 10.1002/brb3.1408
    1. Yang M, Tan H, Zhang K, Lian N, Yu Y, Yu Y. Protective effects of Coenzyme Q10 against sevoflurane-induced cognitive impairment through regulating apolipoprotein E and phosphorylated Tau expression in young mice. Int J Dev Neurosci. 2020; 80:418–28. 10.1002/jdn.10041
    1. Liu Z, Dai X, Zhang H, Shi R, Hui Y, Jin X, Zhang W, Wang L, Wang Q, Wang D, Wang J, Tan X, Ren B, et al.. Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat Commun. 2020; 11:855. 10.1038/s41467-020-14676-4
    1. Nadal A, Quesada I, Tudurí E, Nogueiras R, Alonso-Magdalena P. Endocrine-disrupting chemicals and the regulation of energy balance. Nat Rev Endocrinol. 2017; 13:536–46. 10.1038/nrendo.2017.51
    1. Yu F, Han W, Zhan G, Li S, Xiang S, Zhu B, Jiang X, Yang L, Luo A, Hua F, Yang C. Abnormal gut microbiota composition contributes to cognitive dysfunction in streptozotocin-induced diabetic mice. Aging (Albany NY). 2019; 11:3262–79. 10.18632/aging.101978
    1. Dimova LG, Zlatkov N, Verkade HJ, Uhlin BE, Tietge UJ. High-cholesterol diet does not alter gut microbiota composition in mice. Nutr Metab (Lond). 2017; 14:15. 10.1186/s12986-017-0170-x
    1. Prager O, Friedman A, Nebenzahl YM. Role of neural barriers in the pathogenesis and outcome of Streptococcus pneumoniae meningitis. Exp Ther Med. 2017; 13:799–809. 10.3892/etm.2017.4082
    1. Watanabe I, Kuriyama N, Miyatani F, Nomura R, Naka S, Nakano K, Ihara M, Iwai K, Matsui D, Ozaki E, Koyama T, Nishigaki M, Yamamoto T, et al.. Oral Cnm-positive Streptococcus Mutans Expressing Collagen Binding Activity is a Risk Factor for Cerebral Microbleeds and Cognitive Impairment. Sci Rep. 2016; 6:38561. 10.1038/srep38561
    1. Guo H, Chou WC, Lai Y, Liang K, Tam JW, Brickey WJ, Chen L, Montgomery ND, Li X, Bohannon LM, Sung AD, Chao NJ, Peled JU, et al.. Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science. 2020; 370:eaay9097. 10.1126/science.aay9097
    1. Barichella M, Severgnini M, Cilia R, Cassani E, Bolliri C, Caronni S, Ferri V, Cancello R, Ceccarani C, Faierman S, Pinelli G, De Bellis G, Zecca L, et al.. Unraveling gut microbiota in Parkinson’s disease and atypical Parkinsonism. Mov Disord. 2019; 34:396–405. 10.1002/mds.27581
    1. Bajaj JS, Fagan A, White MB, Wade JB, Hylemon PB, Heuman DM, Fuchs M, John BV, Acharya C, Sikaroodi M, Gillevet PM. Specific Gut and Salivary Microbiota Patterns Are Linked With Different Cognitive Testing Strategies in Minimal Hepatic Encephalopathy. Am J Gastroenterol. 2019; 114:1080–90. 10.14309/ajg.0000000000000102
    1. Pérez-Burillo S, Pastoriza S, Fernández-Arteaga A, Luzón G, Jiménez-Hernández N, D’Auria G, Francino MP, Rufián-Henares JÁ. Spent Coffee Grounds Extract, Rich in Mannooligosaccharides, Promotes a Healthier Gut Microbial Community in a Dose-Dependent Manner. J Agric Food Chem. 2019; 67:2500–09. 10.1021/acs.jafc.8b06604
    1. Louis S, Tappu RM, Damms-Machado A, Huson DH, Bischoff SC. Characterization of the Gut Microbial Community of Obese Patients Following a Weight-Loss Intervention Using Whole Metagenome Shotgun Sequencing. PLoS One. 2016; 11:e0149564. 10.1371/journal.pone.0149564
    1. Zhan G, Yang N, Li S, Huang N, Fang X, Zhang J, Zhu B, Yang L, Yang C, Luo A. Abnormal gut microbiota composition contributes to cognitive dysfunction in SAMP8 mice. Aging (Albany NY). 2018; 10:1257–67. 10.18632/aging.101464
    1. Sturman DA, Moghaddam B. The neurobiology of adolescence: changes in brain architecture, functional dynamics, and behavioral tendencies. Neurosci Biobehav Rev. 2011; 35:1704–12. 10.1016/j.neubiorev.2011.04.003
    1. Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJ, Li G, Sun LS. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012; 130:e476–85. 10.1542/peds.2011-3822
    1. Li Y, Liu C, Zhao Y, Hu K, Zhang J, Zeng M, Luo T, Jiang W, Wang H. Sevoflurane induces short-term changes in proteins in the cerebral cortices of developing rats. Acta Anaesthesiol Scand. 2013; 57:380–90. 10.1111/aas.12018
    1. Burnett S, Sebastian C, Cohen Kadosh K, Blakemore SJ. The social brain in adolescence: evidence from functional magnetic resonance imaging and behavioural studies. Neurosci Biobehav Rev. 2011; 35:1654–64. 10.1016/j.neubiorev.2010.10.011
    1. Desbonnet L, Clarke G, Traplin A, O’Sullivan O, Crispie F, Moloney RD, Cotter PD, Dinan TG, Cryan JF. Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain Behav Immun. 2015; 48:165–73. 10.1016/j.bbi.2015.04.004
    1. Song SY, Meng XW, Xia Z, Liu H, Zhang J, Chen QC, Liu HY, Ji FH, Peng K. Cognitive impairment and transcriptomic profile in hippocampus of young mice after multiple neonatal exposures to sevoflurane. Aging (Albany NY). 2019; 11:8386–417. 10.18632/aging.102326
    1. Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, Sun D, Baxter MG, Zhang Y, Xie Z. Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology. 2013; 118:502–15. 10.1097/ALN.0b013e3182834d77
    1. Farzi A, Fröhlich EE, Holzer P. Gut Microbiota and the Neuroendocrine System. Neurotherapeutics. 2018; 15:5–22. 10.1007/s13311-017-0600-5
    1. Parker A, Lawson MA, Vaux L, Pin C. Host-microbe interaction in the gastrointestinal tract. Environ Microbiol. 2018; 20:2337–53. 10.1111/1462-2920.13926
    1. Hernández-Chirlaque C, Aranda CJ, Ocón B, Capitán-Cañadas F, Ortega-González M, Carrero JJ, Suárez MD, Zarzuelo A, Sánchez de Medina F, Martínez-Augustin O. Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis. J Crohns Colitis. 2016; 10:1324–35. 10.1093/ecco-jcc/jjw096
    1. Liufu N, Liu L, Shen S, Jiang Z, Dong Y, Wang Y, Culley D, Crosby G, Cao M, Shen Y, Marcantonio E, Xie Z, Zhang Y. Anesthesia and surgery induce age-dependent changes in behaviors and microbiota. Aging (Albany NY). 2020; 12:1965–86. 10.18632/aging.102736
    1. de Vos WM, de Vos EA. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutr Rev. 2012. (Suppl 1); 70:S45–56. 10.1111/j.1753-4887.2012.00505.x
    1. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012; 489:220–30. 10.1038/nature11550
    1. Adlerberth I, Wold AE. Establishment of the gut microbiota in Western infants. Acta Paediatr. 2009; 98:229–38. 10.1111/j.1651-2227.2008.01060.x
    1. Marques TM, Wall R, Ross RP, Fitzgerald GF, Ryan CA, Stanton C. Programming infant gut microbiota: influence of dietary and environmental factors. Curr Opin Biotechnol. 2010; 21:149–56. 10.1016/j.copbio.2010.03.020
    1. Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R, Angenent LT, Ley RE. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA. 2011. (Suppl 1); 108:4578–85. 10.1073/pnas.1000081107
    1. Borre YE, Moloney RD, Clarke G, Dinan TG, Cryan JF. The impact of microbiota on brain and behavior: mechanisms and therapeutic potential. Adv Exp Med Biol. 2014; 817:373–403. 10.1007/978-1-4939-0897-4_17
    1. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012; 13:701–12. 10.1038/nrn3346
    1. Falony G, Vieira-Silva S, Raes J. Richness and ecosystem development across faecal snapshots of the gut microbiota. Nat Microbiol. 2018; 3:526–28. 10.1038/s41564-018-0143-5
    1. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005; 308:1635–38. 10.1126/science.1110591
    1. Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 2009; 110:628–37. 10.1097/ALN.0b013e3181974fa2
    1. Tao G, Zhang J, Zhang L, Dong Y, Yu B, Crosby G, Culley DJ, Zhang Y, Xie Z. Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3β activation in young mice. Anesthesiology. 2014; 121:510–27. 10.1097/ALN.0000000000000278
    1. Zhong JY, Magnusson KR, Swarts ME, Clendinen CA, Reynolds NC, Moffat SD. The application of a rodent-based Morris water maze (MWM) protocol to an investigation of age-related differences in human spatial learning. Behav Neurosci. 2017; 131:470–82. 10.1037/bne0000219
    1. Ge X, Zhao W, Ding C, Tian H, Xu L, Wang H, Ni L, Jiang J, Gong J, Zhu W, Zhu M, Li N. Potential role of fecal microbiota from patients with slow transit constipation in the regulation of gastrointestinal motility. Sci Rep. 2017; 7:441. 10.1038/s41598-017-00612-y
    1. Yang C, Fujita Y, Ren Q, Ma M, Dong C, Hashimoto K. Bifidobacterium in the gut microbiota confer resilience to chronic social defeat stress in mice. Sci Rep. 2017; 7:45942. 10.1038/srep45942
    1. Magoč T, Salzberg SL. FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics. 2011; 27:2957–63. 10.1093/bioinformatics/btr507
    1. Yoon SH, Ha SM, Kwon S, Lim J, Kim Y, Seo H, Chun J. Introducing EzBioCloud: a taxonomically united database of 16S rRNA gene sequences and whole-genome assemblies. Int J Syst Evol Microbiol. 2017; 67:1613–17. 10.1099/ijsem.0.001755
    1. Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C. Metagenomic biomarker discovery and explanation. Genome Biol. 2011; 12:R60. 10.1186/gb-2011-12-6-r60

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel