Authors: Khan, Zeeshan A. et al.
Anesthesiology, September 10, 2025. DOI: 10.1097/ALN.0000000000005745
This experimental study explored how the brain–gut–microbiome (BGM) axis may contribute to the intergenerational neurocognitive effects of sevoflurane exposure. The researchers had previously shown that sevoflurane administered to adult male rats can cause learning and memory deficits not only in the exposed animals but also in their male offspring. This study examined whether those effects are associated with alterations in gut microbiota and hippocampal gene expression and whether pharmacologic interventions could prevent them.
Male rats (F0 generation) were exposed to 2.1% sevoflurane for three hours on postnatal days 56, 58, and 60. Before each exposure, some groups received either bumetanide, an NKCC1 chloride transporter inhibitor, or RU486, a glucocorticoid receptor antagonist. These males were later mated to produce offspring (F1 generation), whose brain and gut characteristics were evaluated through RNA sequencing and 16S rRNA microbiome profiling.
Male offspring of sevoflurane-exposed sires exhibited significant abnormalities, including increased corticosterone response to stress, elevated inflammatory markers, altered hippocampal gene expression, gut microbiota dysbiosis, higher LDL cholesterol levels, and increased body weight. Female offspring, by contrast, showed only changes in microbial diversity. Pretreatment of sires with bumetanide or RU486 largely prevented these abnormalities, except for persistent weight gain in male offspring.
These findings suggest that paternal sevoflurane exposure induces epigenetic and microbiome-mediated changes that disrupt the BGM axis and affect offspring health and cognition. Pharmacologic modulation of glucocorticoid signaling or chloride transport before exposure may offer a potential preventive approach.
What You Should Know:
Paternal exposure to sevoflurane can cause intergenerational neurocognitive and metabolic disturbances linked to the brain–gut–microbiome axis, with male offspring most affected. Pretreatment with bumetanide or RU486 significantly reduces these effects, highlighting potential therapeutic avenues for mitigating anesthesia-related heritable risks.
Thank you to Anesthesiology for publishing this important work linking anesthetic exposure, the gut microbiome, and intergenerational neurodevelopmental outcomes.