Alteration of gut microbial ecology by direct activation of the brain: inverse gut-microbiome-brain dynamics

Gut microbes play a crucial role in shaping host physiology and overall fitness. We and others have recently found that selective microbes in the gut can modulate brain function and behavior in a quite powerful way (bottom-up modulation) in both animal models and humans. While bidirectional communication between the gut microbiome and the brain has been described, direct evidence that the brain can modulate the gut microbial ecology (top-down modulation) remains elusive. Here, by combining a brain-centered chemical genetic approach with metagenomic sequencing, we report that direct and persistent stimulation of a brain region implicated in depression leads to changes in the gut microbiome. Selective expression of the bacterial ion channel mNaChBac in glutamatergic lateral habenula (LHb) neurons increases their bursting activity and leads to endophenotypes associated with depression. More importantly, this persistent and selective stimulation in this brain circuit leads to alterations in the gut microbiome composition over time, as reflected by changes in alpha-diversity and alterations in selective microbial taxa. Thus, our findings provide direct evidence that persistent activation of the brain can act as a selective pressure that affects the stability and diversity of the gut microbial ecosystem, providing a new dimension by which gut-microbiome-brain interactions may cooperate to modulate host physiology and health.