The gut microbiota-metabolites-brain axis mediates social behavior dysfunction

A new study from the Air Force Medical University, China shows that Sevoflurane (Sev) influences social functioning via the gut-brain axis, with microbiota-derived bile acids serving as critical mediators in this pathway. This insight offers novel avenues for investigating the mechanisms underlying Sev toxicity and its prevention.

Thousands of infants and children receive general anesthesia (GA) each year for surgery or diagnostic procedures. Evidence from numerous animal studies including nonhuman primates, suggests that Sev exposure, especially during early neurodevelopmental stages, should have the potential to cause multiple neurofunctional changes in the developing brain.

“Our research therefore highlights the role of the gut-microbiota-metabolite-brain axis in Sev mediating neurotoxicity during neonatal period." said Hui Zhang, the leader of the study. “It suggests that remodeling this axis should be a potential therapeutic strategy for preventing neurotoxicity produced by Sev exposure during development.”

The study was published on Sep. 19 in Research, the first Science Partner Journal recently launched by the American Association for the Advancement of Science (AAAS) in collaboration with the China Association for Science and Technology (CAST). Zhang is a professor at the Anesthesiology Department of the Third Affiliated Hospital of the Air Force Medical University.

Increasing evidence suggests that the direct effects of Sev on neurons alone cannot fully explain the pathogenesis of Sev induced developmental neurotoxicity. pathogenesis of Sev induced neurotoxicity may attribute to systemic processes with multiple pathways or targets. Therefore, Zhang and her team looked to the gut microbiota.

“A correlation has been demonstrated between anesthesia exposure and gut microbiota dysbiosis.” Zhang said. “A significant difference between the Sev exposure model and healthy controls was noted in gut microbiota composition and diversity.”

To determine the influence of gut microbiota on Sev neurotoxicity, the team performed fecal microbiota transplantation (FMT) in young mice after Sev exposure. The results showed that the loss of synaptic number and decrease in synaptic complexity caused by Sev was significantly rescued after FMT, and FMT also improved the performance of Sev mice on the social behavior tests. Zhang said Microbial transplantation may regulate the metabolic pathways and production of metabolites in the gut microbiota, and then affect the host through circulation.

The total bile acids levels in the mice serum and fecal were similar to normal ones after FMT. Zhang said that due to the association between bile acids and cognitive function, regulating this metabolite may alleviate Sev induced neurotoxicity. Zhang and her team regulated the levels of bile acids in the gut of mice through cholestyramine (CR). The results showed that CR treatment increased the number and length of asymmetric synapses and spine density, and increased interaction time of Sev-treated mice with stranger mice. Zhang said these data indicate that downregulation of intestinal bile acids can alleviate neuronal synaptic and social function damage caused by Sev.

“Our subsequent research findings indicate that inhibiting the bile acid receptor TGR5 in neuronal cells may ameliorate Sev-induced neurotoxicity.” Zhang noted. “This finding further corroborates the hypothesis that the gut microbiota-metabolite-brain axis plays a role in Sev-induced neurotoxicity.”

Further research is needed in the future to show microbiome-dependence of anesthetic-induced neurotoxicity. Zhang believes that future mechanistic studies should aim to investigate the therapeutic effect of supplementation with specific probiotics on Sev induced neurotoxicity. Zhang said although our research findings suggest that gut microbiota bile acids are important factors in Sev induced social dysfunction, other related pathways in the gut brain axis may also contribute to the neurotoxicity of Sev.

Next, Zhang will continue to undertake additional basic and clinical research aimed at advancing the prevention or treatment of Sev neurotoxicity through the regulation of microbial metabolism. 

“In our hospital, pediatric patients may experience medical conditions necessitating surgical intervention or anesthesia administration. At this time, parents frequently inquire whether general anesthesia will impact their child's brain or future cognitive abilities.” Zhang said. “These parental concerns are also a focal point for us, as anesthesiologists.”