Primate gut microbiota induce evolutionarily salient changes in mouse neurodevelopment.

Differences in brain gene expression between mice inoculated with human versus macaque GMs resemble those observed between actual human and macaque brains.

• Germ-free mice were used as recipients to isolate the effects of the gut microbiota from host genetics and environment.
• The comparison was made between mice colonized with human GMs and mice colonized with macaque GMs.
• This finding suggests that GM composition alone can recapitulate some species-level differences in brain gene expression.
• The result implies a conserved relationship between gut microbiota and brain transcriptional profiles across primate evolution.

The GMs from the two larger-brained primate species (humans and squirrel monkeys) similarly upregulated genes associated with energy production in mouse brains, despite greater evolutionary distance between these species.

• Three primate species were selected to disentangle encephalization from phylogenetic relatedness: humans (large-brained, Catarrhini), macaques (smaller-brained, Catarrhini), and squirrel monkeys (large-brained, Platyrrhini).
• Humans and squirrel monkeys are more distantly related to each other than either is to macaques, yet their GMs had convergent effects on energy production gene expression.
• The convergent upregulation of energy production genes suggests a potential functional link between GM composition and cerebral energy supply in large-brained primates.
• This pattern parallels the known coevolution of large primate brains with metabolic adaptations that enhance cerebral energy supply.

Human GMs specifically increased the expression of genes involved in oxidative phosphorylation in mouse brains.

• This effect was specific to human GMs compared to macaque and squirrel monkey GMs.
• The gene expression changes in oxidative phosphorylation correlated with increased abundances of GM metabolic pathways related to glucose metabolism and gluconeogenesis.
• Oxidative phosphorylation is the primary pathway for ATP production, which is critical for brain energy demands.
• The correlation with glucose metabolism pathways suggests a mechanistic link between gut microbial metabolism and brain energy gene expression.

Human GMs downregulated evolutionarily conserved genes implicated in neurodevelopmental disorders such as autism in mouse brains.

• The downregulated genes were described as 'evolutionarily conserved,' suggesting their relevance across mammalian species.
• These genes are implicated in neurodevelopmental disorders including autism.
• This finding adds a neurodevelopmental dimension to the effects of human-specific GM composition beyond metabolic effects.
• The authors note these findings are based on a small sample of primate species and must be interpreted as preliminary.

The study used germ-free mice inoculated with gut microbiota from three primate species selected to separate the effects of encephalization from phylogenetic relatedness.

• Species selected were humans (large-brained, Catarrhini), macaques (smaller-brained, Catarrhini), and squirrel monkeys (large-brained, Platyrrhini).
• Germ-free mice were used to eliminate confounding effects of host endogenous microbiota.
• This design allowed the authors to distinguish GM effects related to brain size (encephalization) from those related to shared evolutionary history (phylogenetic relatedness).
• The experimental framework enabled causal inference about the role of GM composition in shaping brain gene expression.

The gut microbiota's potential role in primate brain evolution is suggested by the finding that GM composition can influence brain metabolism in ways that parallel known metabolic adaptations associated with large primate brains.

• Multiple primate species including humans evolved brains that are exceptionally large relative to body size.
• These large brains coevolved with metabolic adaptations that enhance cerebral energy supply, including increased circulating glucose levels.
• The GM is known to influence host metabolism, providing a plausible mechanistic pathway.
• The authors raise the possibility that 'the GM could have played a supporting role in primate encephalization,' while noting findings are preliminary given the small sample of primate species.