Stress-related psychiatric disorders often involve disruptions in circadian rhythms and gut microbiota, forming a self-reinforcing cycle: stress disrupts circadian cycles, which further dysregulates the gut microbiota, exacerbating stress responses. However, how the gut microbiota directly influences brain function, stress response, and circadian rhythms remains unclear1. With modern lifestyles characterized by irregular sleep patterns and chronic stress, understanding this complex relationship could provide key insights into improving mental and physical health.

 

The link between circadian rhythms, stress, and the gut microbiota

Stress is triggered by environmental stimuli that activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased glucocorticoid secretion. The HPA axis is the body’s central stress response system, regulating the release of glucocorticoids such as cortisol and corticosterone. These hormones follow a circadian rhythm, peaking at the transition between sleep and wakefulness. This rhythm is controlled by the suprachiasmatic nucleus (SCN), the body’s master clock located in the hypothalamus.

The SCN synchronizes circadian functions through a feedback loop of core clock genes, ensuring that physiological processes align with the 24-hour light-dark cycle. One of the key functions of the SCN is maintaining the appropriate diurnal rhythmicity of glucocorticoids, which helps regulate metabolism, immune function, and stress adaptation. In addition to HPA’s role in both stress and circadian regulation, the HPA axis is a key pathway influenced by the gut microbiota. Indeed, the gut microbiota can influence the HPA axis through the secretion of metabolites that reach the blood-brain barrier and affect various pathways, among which those involved in stress regulation. It is important to note that the gut microbiota follows its own daily oscillations2.

New findings in Cell Metabolism3 by Dr. Cryan and his group, revealed that by regulating corticosterone rhythms, influencing stress-related brain pathways, and modulating time-specific stress responsivity, gut microbes help maintain a balanced interaction between the circadian and HPA systems. Disrupting this microbial balance leads to abnormal stress hormone regulation, potentially increasing vulnerability to stress-related disorders.

Although it is well known that the gut microbiota influences stress responses, the underlying mechanisms remained uncertain. Researchers at APC Microbiome Ireland, led by Dr. Cryan, sought to establish a causal link between gut microbes and the circadian-stress axis. Using germ-free and antibiotic-treated mice, they investigated how the presence or absence of gut microbes affected corticosterone release, gene expression in stress-regulating brain regions, and behavioral responses to stress2.

 

The gut microbiota regulates the diurnal rhythms of glucocorticoids

Through a first set of experiments, the authors not only confirmed that the gut microbiota itself follows diurnal oscilations, but also showed that it regulated the diurnal rhythms in glucocorticoids. In mice with intact microbiota, corticosterone levels followed a predictable rhythm, peaking at the start of the active phase. However, in germ-free and antibiotic-treated mice, this rhythmicity was disrupted, with an exaggerated peak at inappropriate times of the day. The findings suggest that the microbiota helps regulate corticosterone release to align with the body’s natural circadian cycle.

 

Microbial depletion disrupts stress pathway rhythms in the brain

The researchers found that microbial depletion altered the expression of core clock genes. The authors performed transcriptomics and metabolomics of the suprachiasmatic nucleus in the hypothalamus, the hippocampus and the amygdala, which are brain regions crucial for circadian and stress regulation. In the SCN, which orchestrates circadian rhythms, gene expression became desynchronized in germ-free and antibiotic-treated mice. Similar disruptions occurred in the hippocampus and amygdala, where genes involved in stress adaptation lost their normal rhythmic patterns. Additionally, glutamate metabolism, an abundant neurotransmitter in both the hippocampus and amygdala, and key to maintaining appropriate stress responses, was disrupted, suggesting that microbiota depletion weakens the brain’s ability to maintain stable neurotransmitter cycles.

 

Microbial depletion impairs stress responsivity in a time-specific manner

When subjected to acute stress, healthy control mice exhibited appropriate corticosterone increases and accompanying changes in social behaviour regardless of the time of day. However, in microbiota-depleted mice, the ability to mount a proper stress response and related changes in social behaviour depended on the time of testing. At certain points in the circadian cycle, stressed mice failed to show the expected corticosterone surge and social impairment. This indicates that gut microbes help fine-tune the stress response depending on the time of day.

 

Diurnal oscillations of gut microbes directly modulate corticosterone release

Further supporting the role of gut microbiota in circadian-stress regulation, the researchers demonstrated using that the presence of specific bacteria, particularly Lactobacillus species such as Limosilactobacillus reuteri, influenced corticosterone rhythms. This highlights the potential of targeting gut microbiota as a strategy for modulating stress responses and restoring circadian balance.

The study’s findings highlight that modulation of stress responses and behavior by gut microorganisms involve the circadian system. Understanding how the circadian cycle, stress and gut microbiota are linked provide a first step in managing chronic stress and stress related diseases such as depression. The close interaction between stress, the microbiota, and circadian biology may lead to new microbiota-targeting strategies, such as diet4 or probiotic therapy5,6, for stress and sleep-related disorders.

 

Reference:

  1. Cryan JF. Gut microbiota: our fellow travellers in health & disease. FEBS J. 2025;292:1223–1227. https://doi.org/10.1111/febs.70045
  2. Tofani GSS, Clarke G, Cryan JF. I “Gut” Rhythm: the microbiota as a modulator of the stress response and circadian rhythms. FEBS J. 2025;292:1454–1479. https://doi.org/10.1111/febs.17400
  3. Tofani GSS, Leigh SJ, Gheorghe CE, et al. Gut microbiota regulates stress responsivity via the circadian system. Cell Metab. 2025;37:138–153.e5. https://doi.org/10.1016/j.cmet.2024.10.003
  4. Berding K, Bastiaanssen TFS, Moloney GM, et al. Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population. Mol Psychiatry. 2023;28(2):601–610. https://doi.org/10.1038/s41380-022-01692-7
  5. Zhang N, Zhang Y, Li M, et al. Efficacy of probiotics on stress in healthy volunteers: a systematic review and meta-analysis based on randomized controlled trials. Brain Behav. 2020;10:e01699. https://doi.org/10.1002/brb3.1699
  6. Ma T, Jin H, Kwok L-Y, et al. Probiotic consumption relieved human stress and anxiety symptoms possibly via modulating the neuroactive potential of the gut microbiota. Neurobiol Stress. 2021;14:100294. https://doi.org/10.1016/j.ynstr.2021.100294