Tofani Gabriel S S, Leigh Sarah-Jane, Gheorghe Cassandra E, Bastiaanssen Thomaz F S, Wilmes Lars, Sen Paromita, Clarke Gerard, Cryan John F
APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Psychiatry & Neurobehavioral Sciences, University College Cork, Cork, Ireland.
Cell Metab. 2025 Jan 7;37(1):138-153.e5. doi: 10.1016/j.cmet.2024.10.003. Epub 2024 Nov 5.
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.
应激系统和昼夜节律系统通过下丘脑-垂体-肾上腺（HPA）轴相互连接，以维持对外部刺激的反应。然而，这些信号如何协调的机制仍然未知。在这里，我们发现肠道微生物群是HPA轴节律性的调节因子。微生物的缺失会扰乱大脑转录组和代谢组，影响海马体和杏仁核中全天应激反应途径。这与大脑中昼夜节律起搏器的失调有关，进而导致糖皮质激素节律紊乱。在睡眠/觉醒转换时HPA轴的过度激活会导致特定时间的应激反应和应激敏感行为受损。最后，微生物群移植证实肠道微生物的昼夜振荡是糖皮质激素分泌改变的基础，而罗伊氏乳杆菌是产生这种影响的候选菌株。我们的数据提供了令人信服的证据，表明微生物群以昼夜节律的方式调节应激反应，并且是全天对应激源做出适应性反应所必需的。
