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.
Competing Interests: Declaration of interests J.F.C. has been an invited speaker at conferences organized by Bromotech and Nestle and has received research funding from Nutricia, Dupont/IFF, and Nestle. G.C. has received honoraria from Janssen, Probi, and Apsen as an invited speaker; is in receipt of research funding from Pharmavite, Fonterra, Reckitt, Nestle, Tate, and Lyle; and is a paid consultant for Yakult, Zentiva, and Heel Pharmaceuticals. This support neither influenced nor constrained the contents of this article.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)