Contribution of the Brain–Gut–Microbiome Axis to Intergenerational Abnormalities in a Rat Model of Perioperative Neurocognitive Disorder

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, and to various metabolic abnormalities. Recently, the authors reported that sevoflurane induces neurocognitive deficits in exposed rats as well as their future offspring, with male offspring being particularly affected (intergenerational perioperative neurocognitive disorder). In this study, the authors 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 h on postnatal days 56, 58, and 60 (F0M_S group). Before 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. Conclusions: 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.