Gut Microbiota Regulates the Integration of Central Stress and Circadian Signals

Stress and circadian systems are bidirectionally interconnected to maintain appropriate responses to external stimuli. The gut microbiota has been shown to modulate these systems independently, but its role in regulation of the integration of stress and circadian signals remains unknown. With the modern environment involving increasing circadian disruption and stressor exposure, there is a need for a better understanding of how our responses to these constant changes are shaped, and more importantly, how they can be targeted to improve health. In this work we provide compelling evidence that gut microbiota modulation of stress responsiveness exhibits diurnal rhythmicity. From comprehensive bioinformatic analysis of transcriptomics and metabolomics we demonstrate that the diurnal oscillations of the stress relevant pathways are disrupted by modulating the gut microbiota in the suprachiasmatic nucleus, amygdala and hippocampus, key brain regions involved in both central circadian regulation and the behavioural stress response. This was coupled with alterations in the rhythmic profile of glucocorticoid secretion, impaired response to acute stress and altered stress-sensitive behaviours. Moreover, we perform faecal microbiota transfer and show that diurnal oscillations of gut microbes regulate glucocorticoid secretion and unmask the microbial underpinnings of such changes. Thus, the gut microbiota regulates diurnal oscillations of stress responsiveness and is necessary to respond adaptively to psychological stressors throughout the day, which paves the way to explore interventions that can target gut microbes to modulate circadian and stress-related manifestations at the same time.