Influences of the primate gut microbiota on mouse metabolism

Highly encephalized species such as humans require elevated glucose to sustain their high brain energy needs, and there is evidence that this drives a trade-off between providing energy to the brain and storing energy as adiposity across vertebrate species. However, despite its importance for understanding brain evolution, the biological underpinnings of this trade-off are not known. Given the influence of the gut microbiota (GM) on host metabolism, we hypothesized that the GM contributes to variation in metabolic phenotypes across primates with differences in encephalization. By inoculating germ-free mice with the GMs of more- and less-encephalized primates, we demonstrate that the GMs of two distantly related but larger brained primates both stimulate glucose production. In contrast, mice inoculated with the GM of a less-encephalized primate prioritize weight gain and energy storage in adipose tissue. Differences in liver gene expression represent one of the pathways through which the GM induces these phenotypes. These findings establish that the GM plays a causal role in the documented cross-species trade-off between brain energetics and body fat and show that the GM was likely an important metabolic facilitator of human brain evolution.