BACKGROUND: The brain-gut-microbiome (BGM) axis is a communication network through which the brain and gastrointestinal microbiota interact via neural, hormonal, immune, and gene expression mechanisms. Gut microbiota dysbiosis is thought to contribute to neurocognitive disorders, including perioperative neurocognitive disorder (PND), and to various metabolic abnormalities. Recently, we reported that sevoflurane induces neurocognitive deficits in exposed rats as well as their future offspring, with male offspring being particularly affected (intergenerational PND). In this study, we examined in the same animals whether the intergenerational effects of sevoflurane involve abnormalities in the BGM axis, and whether they are mitigated by paternal pretreatment with either the Na+-K+-Cl- (NKCC1) Cl- transporter inhibitor bumetanide or the glucocorticoid receptor inhibitor RU486, as previously demonstrated for neurocognitive deficits. METHODS: Male Sprague Dawley rats (F0 generation) were exposed to 2.1% sevoflurane for 3 hours on postnatal days 56, 58, and 60 (F0M_S group). Prior to each sevoflurane exposure, distinct experimental groups of F0 males received bumetanide (F0M_BS group) or RU486 (F0M_RS group). These males were mated on postnatal day 90 to produce offspring (F1 generation). Gut microbiota were profiled using 16S rRNA gene sequencing, and brain changes analyzed via RNA sequencing of hippocampal samples. RESULTS: F1 male offspring of F0M_S sires exhibited heightened corticosterone responses to stress, increased inflammatory markers, altered hippocampal transcriptomes, gut microbiota dysbiosis, elevated serum low-density lipoprotein cholesterol levels, and increased body weight. The only abnormality observed in F1 females was a shift in microbial diversity. F0M_S displayed profound alterations in hippocampal transcriptome, while microbial diversity was the only parameter affected in their gut microbiota. Bumetanide or RU486 mitigated most abnormalities, except increased body weight in F1 males. CONCLUSION: Paternal sevoflurane exposure in rats induces BGM axis abnormalities, particularly in male offspring, despite the absence of direct anesthetic exposure. Pretreatment with bumetanide or RU486 showed therapeutic efficacy.

Department of Anesthesiology University of Florida College of Medicine Gainesville Florida

Department of Psychiatry University of Florida College of Medicine Gainesville Florida

Laboratory of Genomics and Bioinformatics Institute of Molecular Genetics of the Czech Academy of Sciences Prague 4 Czech Republic

McKnight Brain Institute University of Florida College of Medicine Gainesville Florida

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Cullen KA, Hall MJ, Golosinskiy A: Ambulatory surgery in the United States, 2006. Natl Health Stat Report 2009:1–25 PubMed

National Center for Health Statistics (US), National Hospital Discharge Survey (US): National hospital discharge survey. US Department of Health and Human Services, Centers for Disease Control and; …, 2010

Weiser TG, Haynes AB, Molina G, Lipsitz SR, Esquivel MM, Uribe-Leitz T, Fu R, Azad T, Chao TE, Berry WR, Gawande AA: Size and distribution of the global volume of surgery in 2012. Bull World Health Organ 2016; 94:201–209F PubMed PMC

Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, Oh ES, Crosby G, Berger M, Eckenhoff RG, Nomenclature Consensus Working Group: Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery-2018. Anesthesiology 2018; 129:872–9 PubMed

Monk TG, Weldon BC, Garvan CW, Dede DE, Aa MT van der, Heilman KM, Gravenstein JS: Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108:18–30 PubMed

Daiello LA, Racine AM, Yun Gou R, Marcantonio ER, Xie Z, Kunze LJ, Vlassakov KV, Inouye SK, Jones RN, Alsop D, Travison T, Arnold S, Cooper Z, Dickerson B, Fong T, Metzger E, Pascual-Leone A, Schmitt EM, Shafi M, Cavallari M, Dai W, Dillon ST, McElhaney J, Guttmann C, Hshieh T, Kuchel G, Libermann T, Ngo L, Press D, Saczynski J, et al. : Postoperative delirium and postoperative cognitive dysfunction: overlap and divergence. Anesthesiology 2019; 131:477–91 PubMed PMC

Lage C, González-Suárez A, Alcalde-Hierro MP, Sampedro-González MI, Villanueva-Eguaras MÁ, Sánchez-Crespo MR, Widmann C, Brosseron F, Pozueta A, López-García S, García-Martínez M, Kazimierczak M, Bravo-González M, Fernández-Rodríguez A, Drake-Pérez M, Irure-Ventura J, López-Hoyos M, Rodríguez-Rodríguez E, Heneka MT, Sánchez-Juan P: Major Surgery Affects Memory in Individuals with Cerebral Amyloid-β Pathology. J Alzheimers Dis 2021; 79:863–74 PubMed

Ju L-S, Khan ZA, Gravenstein N, Seubert CN, Setlow B, Martynyuk AE: Intergenerational postoperative neurocognitive disorder in a rat model: initiating mechanisms and pharmacological prevention. Anesthesiology 2025. 10.1097/ALN.0000000000005578 PubMed DOI PMC

Morys J, Małecki A, Nowacka-Chmielewska M: Stress and the gut-brain axis: an inflammatory perspective. Front Mol Neurosci 2024; 17:1415567 PubMed PMC

MacKay M, Yang BH, Dursun SM, Baker GB: The Gut-Brain Axis and the Microbiome in Anxiety Disorders, Post-Traumatic Stress Disorder and Obsessive-Compulsive Disorder. Curr Neuropharmacol 2024; 22:866–83 PubMed PMC

Tan H-E: The microbiota-gut-brain axis in stress and depression. Front Neurosci 2023; 17:1151478 PubMed PMC

Jeong S, Chokkalla AK, Davis CK, Vemuganti R: Post-stroke depression: epigenetic and epitranscriptomic modifications and their interplay with gut microbiota. Mol Psychiatry 2023; 28:4044–55 PubMed PMC

McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL: Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol 2010; 160:1573–6 PubMed PMC

Ju L-S, Yang J-J, Xu N, Li J, Morey TE, Gravenstein N, Seubert CN, Setlow B, Martynyuk AE: Intergenerational effects of sevoflurane in young adult rats. Anesthesiology 2019; 131:1092–109 PubMed PMC

Ju L-S, Zhu J, Brant JO, Morey TE, Gravenstein N, Seubert CN, Vasilopoulos T, Setlow B, Martynyuk AE: Intergenerational Perioperative Neurocognitive Disorder in Young Adult Male Rats with Traumatic Brain Injury. Anesthesiology 2022. 10.1097/ALN.0000000000004496 PubMed DOI PMC

Willis J, Zhu W, Perez-Downes J, Tan S, Xu C, Seubert C, Gravenstein N, Martynyuk A: Propofol-induced electroencephalographic seizures in neonatal rats: the role of corticosteroids and γ-aminobutyric acid type A receptor-mediated excitation. Anesth Analg 2015; 120:433–9 PubMed PMC

Zhang J, Xu C, Puentes DL, Seubert CN, Gravenstein N, Martynyuk AE: Role of steroids in hyperexcitatory adverse and anesthetic effects of sevoflurane in neonatal rats. Neuroendocrinology 2016; 103:440–51 PubMed PMC

Ju L: Intergenerational perioperative neurocognitive disorder in young adult male rats with traumatic brain injury. Dissertation Abstracts International: Section B: The Sciences and Engineering 2024; 85:No-Specified

Gloor GB, Macklaim JM, Pawlowsky-Glahn V, Egozcue JJ: Microbiome datasets are compositional: and this is not optional. Front Microbiol 2017; 8:2224. PubMed PMC

Xia Y, Sun J: Hypothesis testing and statistical analysis of microbiome. Genes Dis 2017; 4:138–48 PubMed PMC

Peterson CB, Saha S, Do K-A: Analysis of microbiome data. Annu Rev Stat Appl 2024; 11:483–504 PubMed PMC

Ma W, Zhang L, Zeng P, Huang C, Li J, Geng B, Yang J, Kong W, Zhou X, Cui Q: An analysis of human microbe-disease associations. Brief Bioinformatics 2017; 18:85–97 PubMed

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:e126–9 PubMed PMC

Han S, Bian R, Chen Y, Liang J, Zhao P, Gu Y, Zhang D: Dysregulation of the Gut Microbiota Contributes to Sevoflurane-Induced Cognitive Dysfunction in Aged Mice by Activating the NLRP3 Inflammasome. Mol Neurobiol 2024; 61:10500–16 PubMed

Liu L, Shang L, Jin D, Wu X, Long B: General anesthesia bullies the gut: a toxic relationship with dysbiosis and cognitive dysfunction. Psychopharmacology (Berl) 2022; 239:709–28 PubMed

Thriene K, Michels KB: Human Gut Microbiota Plasticity throughout the Life Course. Int J Environ Res Public Health 2023; 20 PubMed PMC

Beghetti I, Barone M, Turroni S, Biagi E, Sansavini A, Brigidi P, Corvaglia L, Aceti A: Early-life gut microbiota and neurodevelopment in preterm infants: any role for Bifidobacterium? Eur J Pediatr 2022; 181:1773–7 PubMed

Wu Y, Niu X, Li P, Tong T, Wang Q, Zhang M, Li Y, Liu J, Li Z: Lactobacillaceae improve cognitive dysfunction via regulating gut microbiota and suppressing Aβ deposits and neuroinflammation in APP/PS1 mice. Arch Microbiol 2023; 205:118. PubMed

Peters SJ, Dyck DJ, Bonen A, Spriet LL: Effects of epinephrine on lipid metabolism in resting skeletal muscle. Am J Physiol 1998; 275:E300–9 PubMed

Marqués-Torrejón MÁ, Porlan E, Banito A, Gómez-Ibarlucea E, Lopez-Contreras AJ, Fernández-Capetillo O, Vidal A, Gil J, Torres J, Fariñas I: Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression. Cell Stem Cell 2013; 12:88–100 PubMed PMC

Riazati N, Kable ME, Stephensen CB: Association of intestinal bacteria with immune activation in a cohort of healthy adults. Microbiol Spectr 2023; 11:e0102723 PubMed PMC

Wang H, Wang G, Banerjee N, Liang Y, Du X, Boor PJ, Hoffman KL, Khan MF: Aberrant gut microbiome contributes to intestinal oxidative stress, barrier dysfunction, inflammation and systemic autoimmune responses in mrl/lpr mice. Front Immunol 2021; 12:651191 PubMed PMC

Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A: The genus alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol 2020; 11:906. PubMed PMC

Bello-Medina PC, Corona-Cervantes K, Zavala Torres NG, González A, Pérez-Morales M, González-Franco DA, Gómez A, García-Mena J, Díaz-Cintra S, Pacheco-López G: Chronic-Antibiotics Induced Gut Microbiota Dysbiosis Rescues Memory Impairment and Reduces β-Amyloid Aggregation in a Preclinical Alzheimer’s Disease Model. Int J Mol Sci 2022; 23 PubMed PMC

di Candia AM, de Avila DX, Moreira GR, Villacorta H, Maisel AS: Growth differentiation factor-15, a novel systemic biomarker of oxidative stress, inflammation, and cellular aging: Potential role in cardiovascular diseases. Am Heart J Plus 2021; 9:100046 PubMed PMC

Hidalgo I, Sorolla MA, Sorolla A, Salud A, Parisi E: Secreted phospholipases A2: drivers of inflammation and cancer. Int J Mol Sci 2024; 25 PubMed PMC

Weckbach LT, Muramatsu T, Walzog B: Midkine in inflammation. ScientificWorldJournal 2011; 11:2491–505 PubMed PMC

Zaky A, Glastras SJ, Wong MYW, Pollock CA, Saad S: The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease. Int J Mol Sci 2021; 22 PubMed PMC

Crudele L, Gadaleta RM, Cariello M, Moschetta A: Gut microbiota in the pathogenesis and therapeutic approaches of diabetes. EBioMedicine 2023; 97:104821 PubMed PMC

Abernathy-Close L, Barron MR, George JM, Dieterle MG, Vendrov KC, Bergin IL, Young VB: Intestinal Inflammation and Altered Gut Microbiota Associated with Inflammatory Bowel Disease Render MiceSusceptible to Clostridioides difficile Colonization and Infection. MBio 2021; 12:e0273320 PubMed PMC

Kueh MTW, Chew NWS, Al-Ozairi E, Roux CW le: The emergence of obesity in type 1 diabetes. Int J Obes (Lond) 2024; 48:289–301 PubMed PMC

Tell S, Nadeau KJ, Eckel RH: Lipid management for cardiovascular risk reduction in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2020; 27:207–14 PubMed PMC

Klop B, Elte JWF, Cabezas MC: Dyslipidemia in obesity: mechanisms and potential targets. Nutrients 2013; 5:1218–40 PubMed PMC

Laukoter S, Beattie R, Pauler FM, Amberg N, Nakayama KI, Hippenmeyer S: Imprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development. Nat Commun 2020; 11:195. PubMed PMC