Gut Microbes May Have Helped Fuel the Evolution of Large Brains

How did human brains get so large? The answer might lie in an unexpected place: our gut.

New research from Northwestern University suggests gut microbes may have played a key role in meeting the energy demands of larger brains throughout primate evolution. The study was published in Microbial Genomics.

The human brain is metabolically demanding

The human brain is a marvel of evolution, distinguished by its size and complexity relative to other primates. However, maintaining such a large brain is metabolically demanding. Brain tissue requires around 20 times more energy than equivalent muscle tissue, largely due to functions like neuronal signaling and synapse formation. This creates an evolutionary challenge: how do organisms acquire enough energy to fuel a large brain without compromising other essential processes?

Previous theories have pointed to dietary changes and genetic adaptations to explain this metabolic dilemma. For example, the "Expensive Tissue Hypothesis" suggests that humans evolved smaller digestive systems to offset the energy demands of larger brains, enabled by a shift to higher-quality diets rich in meat and cooked foods. This trade-off reduced the metabolic load on the gut, allowing energy to be redirected to the brain.

Prior studies have focused on comparing the genetic and environmental factors that influence brain size in primates, providing insights into the evolutionary pathways of encephalization. However, there has been limited exploration into how primates with different brain sizes use energy, and even less is known about how metabolic traits develop across species.

“Variation in the gut microbiota is an unexplored mechanism in which primate metabolism could facilitate different brain-energetic requirements,” said lead author Dr. Katherine Amato, an associate professor of anthropology at Northwestern University.

Gut microbial communities influence metabolism by breaking down food, producing energy-rich compounds like short-chain fatty acids and regulating processes such as glucose metabolism and fat storage. Studies in metabolic diseases have shown that gut microbes are closely linked to key host metabolic traits. This suggests that microbiota may influence how organisms meet the energy demands of complex tissues, including the brain.

“We know the community of microbes living in the large intestine can produce compounds that affect aspects of human biology – for example, causing changes to metabolism that can lead to insulin resistance and weight gain,” said Amato.

Impact of gut microbes on energy expenditure and fat storage in mice

Amato and the team transplanted gut microbes from three distinct groups – humans, squirrel monkeys (representing large-brained primates) and macaques (smaller-brained primates) – into germ-free mice. After the microbial transplants, the researchers monitored several physiological and metabolic markers in the mice to assess the impact of the introduced microbiota, including:

• Energy expenditure – to determine how much energy was being used.
• Blood glucose levels – to assess how well the mice could mobilize energy for brain and bodily functions.
• Fat storage – to evaluate energy storage tendencies.
• Post-experiment tissue analysis – to provide further insights into how the energy was allocated or stored in different body compartments, including fat and brain tissue.

The mice that received microbes from humans and squirrel monkeys displayed higher blood glucose levels and an increased rate of energy use – a change that could indicate a metabolic shift towards supporting the energy-intensive needs of larger brains.

In contrast, mice given gut microbes from macaques showed a tendency to store more energy as fat. This pattern suggests a trade-off, where species with smaller brains might rely more heavily on energy reserves rather than immediate energy consumption to meet their metabolic needs.

“While we did see that human-inoculated mice had some differences, the strongest pattern was the difference between large-brained primates (humans and squirrel monkeys) and smaller-brained primates (macaques),” said Amato.

Evolutionary implications of microbial influence on brain development

The study suggests that the gut microbiome may have played a large role in supporting the metabolic demands of larger brains during primate evolution. By influencing energy production, the microbes in species with larger brains, like humans, may have helped meet the high metabolic needs of brain tissue. This offers a new perspective on how gut microbiota could have facilitated the development of human cognitive abilities.

“These findings suggest that when humans and squirrel monkeys both separately evolved larger brains, their microbial communities changed in similar ways to help provide the necessary energy,” said Amato.

The authors hope to expand their research to study microbes from a wider range of primates.

Reference: Mallott EK, Kuthyar S, Lee W, et al. The primate gut microbiota contributes to interspecific differences in host metabolism. Microbial Genomics. 2024. doi: 10.1099/mgen.0.001322

This article is a rework of a press release issued by Northwestern University. Material has been edited for length and content.