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

The gut-microbiome-brain axis is a bidirectional communication system influencing host physiology and overall fitness. While "bottom-up" effects—where gut microbes influence brain function and behavior—are well established, direct evidence for "top-down" modulation—where the brain shapes the gut microbial ecology—remains elusive. Here, we show that selective expression of the bacterial ion channel mNaChBac in glutamatergic lateral habenula (LHb) neurons increases their bursting activity and leads endophentypes associated with depression. Importantly, this chronic activation leads to changes in the gut microbiome composition over time, as reflected by shifts in alpha-diversity and alterations in specific microbial taxa. These findings provide direct evidence that persistent activation of the brain acts as a selective pressure that affects the stability and diversity of the gut microbiome, providing a new dimension by which gut-microbiome-brain interactions may cooperate to modulate host physiology and health. • Persistent LHb activation leads to depression-like phenotypes • Persistent LHb activation drives shifts in gut microbial ecology over time. • Direct proof of top-down control in the gut–brain–microbiota communication.