Gut microbiota regulates stress responsivity via the circadian system

Stress and circadian systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis to maintain responses to external stimuli. Yet, the mechanisms of how such signals are orchestrated remain unknown. Here, we uncover the gut microbiota as a regulator of HPA-axis rhythmicity. Microbial depletion disturbs the brain transcriptome and metabolome in stress-responding pathways in the hippocampus and amygdala across the day. This is coupled with a dysregulation of the circadian pacemaker in the brain that results in perturbed glucocorticoid rhythmicity. The resulting hyper-activation of the HPA axis at the sleep/wake transition drives time-of-day-specific impairments of the stress response and stress-sensitive behaviors. Finally, microbiota transplantation confirmed that diurnal oscillations of gut microbes underlie altered glucocorticoid secretion and that L. reuteri is a candidate strain for such effects. Our data offer compelling evidence that the microbiota regulates stress responsiveness in a circadian manner and is necessary to respond adaptively to stressors throughout the day. • Gut microbiota regulates diurnal rhythms of corticosterone • Microbial depletion leads to disruption in rhythmicity of stress pathways in the brain • Microbial depletion results in time-of-day-specific impairments in stress responsivity • Diurnal oscillations of gut microbes modulate corticosterone release Gut microbes are known to modulate stress responsivity and behavior. Tofani et al. demonstrate that such modulations occur via the circadian system. The oscillations in gut microbiota composition regulate the diurnal rhythmicity of hypothalamic-pituitary-adrenal (HPA)-axis function, which leads to altered stress responsivity across the day.