Scientists have long puzzled over how humans evolved such unusually large, energy-hungry brains. Neurons are expensive. They demand a constant and reliable supply of fuel, particularly glucose, and the human brain consumes a disproportionate share of the body’s energy budget.
Now, a new study suggests that part of the answer may lie not in our genes, but in the microscopic ecosystems living inside our guts.
In a paper published in Proceedings of the National Academy of Sciences, researchers report that gut microbes from different primate species can induce strikingly different patterns of brain gene activity when transferred into mice.
Remarkably, microbes from large-brained primates, including humans, trigger brain changes linked to energy production that mirror evolutionary differences in primate brains.
The findings raise the possibility that shifts in the gut microbiome may have helped support the metabolic demands of expanding brains over the course of evolution.
“This study provides more evidence that microbes may causally contribute to these disorders—specifically, the gut microbiome is shaping brain function during development,” lead author and professor of biological anthropology at Northwestern University, Dr. Katie Amato, said in a press release.
“Based on our findings, we can speculate that if the human brain is exposed to the actions of the ‘wrong’ microbes, its development will change, and we will see symptoms of these disorders, i.e., if you don’t get exposed to the ‘right’ human microbes in early life, your brain will work differently, and this may lead to symptoms of these conditions.”
The study tackles a long-standing problem in evolutionary biology of how primates overcame the energetic constraints of growing bigger brains. Large brains require more glucose, more oxygen, and more metabolic infrastructure to keep neurons firing and synapses functioning.
While previous research has identified genetic and physiological adaptations that support these demands, the potential role of gut microbes, a major regulator of host metabolism, has remained largely unexplored.
To investigate this, researchers designed an unusual experiment. They raised germ-free mice and inoculated them with gut microbiota from three different primate species chosen to disentangle brain size from evolutionary relatedness: humans, macaques, and squirrel monkeys.
Humans and squirrel monkeys both have relatively large brains for their body size, despite being distantly related, whereas macaques, which are more closely related to humans, have smaller brains relative to body size.
After allowing the transplanted microbiomes to establish, the researchers analyzed gene expression in the mice’s frontal cortex, a brain region involved in higher-order cognition and decision-making.
What they found was that differences in brain gene expression between mice given human versus macaque gut microbes closely resembled those seen between actual human and macaque brains.
“Brain gene expression differences between mice inoculated with human versus macaque GMs mirrored patterns observed in human versus macaque brains,” the researchers write. That parallel, they argue, suggests that gut microbes can influence brain biology in ways that align with evolutionary divergence across species.
When the team compared the effects of microbiota from all three primate species, they found that microbes from the two large-brained species, humans and squirrel monkeys, produced more similar brain gene expression patterns in mice than either did compared to macaques. In other words, microbiomes from distantly related but highly encephalized primates converged on similar effects in the brain.
Researchers say the effects were not random. Genes upregulated in mice carrying human gut microbes were strongly associated with oxidative phosphorylation and glucose metabolism—core processes involved in producing energy within cells. These pathways are known to be especially important in the brain, where energy demands are high and constant.
Researchers also linked these brain changes to functional differences in the gut microbiome itself. Microbial pathways involved in glucose degradation and gluconeogenesis, the production of glucose from non-carbohydrate sources, were more abundant in human-derived microbiomes and were statistically associated with increased expression of energy-related genes in the mouse brain.
Together, these findings suggest a coordinated gut–brain metabolic axis in which microbial activity influences the amount of fuel the brain can access and use.
Intriguingly, the study also found that human gut microbes downregulated certain evolutionarily conserved genes associated with neurodevelopmental disorders.
Genes that were more highly expressed in mice with macaque microbiota were enriched for associations with conditions such as autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia. In contrast, mice with human microbiota showed reduced expression of many of these genes.
Researchers caution that these results should not be overinterpreted, but they note that the pattern is consistent with previous findings showing that genes involved in synaptic signaling and neurodevelopment are often under strong evolutionary constraint.
In the paper, researchers write that “human GMs also downregulated evolutionarily conserved genes implicated in neuro-developmental disorders such as autism,” highlighting a potential role for the microbiome in modulating genes critical for typical brain development.
Researchers also examined where in the brain these metabolic changes might matter most. By comparing maps of oxidative phosphorylation gene expression with maps of cortical regions that expanded most during human evolution, they found significant spatial overlap.
Regions that grew disproportionately larger in humans than in macaques were also regions with higher expression of energy-production genes. This alignment supports the idea that metabolic demands and brain expansion evolved hand in hand, and that the gut microbiome may have been part of that story.
Importantly, the study does not claim that gut microbes drove brain evolution on their own. Researchers explicitly acknowledge the limitations of their work, noting the small number of primate species included and the indirect nature of the mouse model.
Although these are findings based on a small sample of primate species and must be interpreted as preliminary, they suggest that species differences in GM composition can influence brain metabolism and raise the possibility that the GM could have played a supporting role in primate encephalization,” researchers write.
Genetic changes, dietary shifts, life-history traits, and many other factors undoubtedly played major roles in primate brain evolution.
Nevertheless, the findings open a new window into how evolution operates across biological systems. Rather than viewing the brain as evolving in isolation, the study highlights the possibility that microbial partners – passed across generations and shaped by diet, ecology, and behavior -may have helped enable one of the most distinctive features of the human lineage.
If future studies confirm and extend these findings across more species, the implications could be far-reaching. Understanding how gut microbes influence brain metabolism may shed light not only on human evolution, but also on modern brain health, neuro-developmental disorders, and the subtle ways in which our microbial companions continue to shape who we are.
For now, the study adds to a growing body of evidence that evolution’s fingerprints are not limited to our own cells. They may also be written in the genomes of the trillions of microbes that have traveled with us through deep time—quietly helping to fuel the brains that define us as humans.
“Although our results provide a valuable contribution to understanding the physiological correlates of encephalization in primates,” the researchers conclude. “These findings are consistent with the hypothesis that gut microbial differences could have supported metabolic and other demands associated with primate and human encephalization, but additional studies will be needed to test this idea directly.”
Tim McMillan is a retired law enforcement executive, investigative reporter and co-founder of The Debrief. His writing typically focuses on defense, national security, the Intelligence Community and topics related to psychology. You can follow Tim on Twitter: @LtTimMcMillan. Tim can be reached by email: tim@thedebrief.org or through encrypted email: LtTimMcMillan@protonmail.com