Human gut microbiota and brain evolution

The human brain is a notable organ, honed by millions of years of natural selection for cognition.It has evolved from less than 500 cc in volume in ancestral hominins to over 1,200 cc in modern Homo sapiens (1), gaining neurons along the way (2) and undergoing substantial structural reorganization (3).Like other complex traits, the human brain is shaped by gene expression-the processes by which functional products, such as proteins and RNA molecules, are produced from coding regions of the genome.Comparative studies have mapped differences in brain gene expression between humans and nonhuman primates (NHPs) (4), and experimental work has probed specific genetic mutations that have contributed to these differences (5).For instance, the human genome has lost an enhancer that promotes expression of GADD45G, a protein that represses neuronal proliferation, and gene-editing studies in mice have shown that deletion of the murine homolog of this enhancer is sufficient to recapitulate derived features of human brain development (6).Alongside genetic mutations, myriad epigenetic factors, such as culture, diet, and microbial symbionts, may contribute to the uniqueness of the human brain's gene expression profile (7).However, these epigenetic contributions have been more difficult to assess, due to the lack of experiments that manipulate individual factors under otherwise consistent environmental conditions.In this issue, DeCasien et al. (8) report results of experiments in gnotobiotic (known-life) mice, in which microbial exposures can be precisely manipulated, providing evidence that gut microbes have driven frontal cortex gene expression divergence between humans and NHPs (Fig. 1).