Gut microbiota may regulate stress response via our body clocks: Study

Scientists at APC Microbiome Ireland, University College Cork, note the potential for psychobiotic therapies for mental health conditions, which are often associated with sleep disruption.

“The gut microbiome doesn’t just regulate digestion and metabolism; it plays a critical role in how we react to stress, and this regulation follows a precise circadian rhythm.” Professor John Cryan, principal investigator, stated in a press release. 

The findings expand the evidence for the gut-brain axis in mental health, adding to APC’s extensive research into microbial solutions for health and disease and collaborations with industry to develop science-based products. 

Stress and circadian systems are intertwined

The circadian and stress systems are linked as an evolutionary adaptation to allow us to respond to the environment.

Although the two systems have different functions, they share a common information pathway: The hypothalamic-pituitary-adrenal (HPA) axis. Additionally, some of their key control centers—the suprachiasmatic nucleus (SCN) and the paraventricular nucleus of the hypothalamus—are close in proximity and interconnected.

Circadian rhythms and stress activate the HPA axis, releasing glucocorticoids such as cortisol. Cortisol is the primary stress hormone, having physiological effects on the body to produce a fight or flight response and control inflammation. 

Glucocorticoids peak as we wake from sleep, acting as a cue to the rest of the body. The SCN maintains the rhythmic pattern of glucocorticoids, which can vary according to the time of day and the efficiency of someone’s stress response.

Gut-brain axis rhythms

The current study notes that previous research has linked psychiatric disorders to disruption in internal clocks and the balance of gut bacteria. 

It expands the mechanisms of the gut-brain axis and its rhythmicity, demonstrating that gut bacteria depletion affects the brain's circadian clocks and upsets the normal rhythm of stress hormones. This results in hyper-activation of the HPA axis at the sleep/wake transition, which results in impaired stress responses and stress-sensitive behaviors.

“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,” the researchers wrote.

Study details

The study analyzed transcriptomic and metabolomic data of mice to evaluate the connections between gut bacteria, stress response and circadian rhymes.

The researchers confirmed by metagenomic sequencing that gut microbes oscillate throughout the day, in particular the Lactobacillus strain, which includes species commonly used as probiotics such as Limosilactobacillus reuteri and Lactobacillus jensenii.

They found that in germ-free mice, the usual peak phase of corticosterone shifted to the dark phase, altering master-clock rhythmicity. Manipulating gut microbes altered the “rhythmicity of stress pathways in regions key for regulating the stress response” and brain glutamate metabolism.

The study further established that gut microbiota modulates the rhythms of the HPA axis, showing hyper-activation at the circadian peak and a permeable blood-brain barrier. In terms of behavior, the mice exhibited a blunted corticosterone release, leading to “impairments in stress-sensitive social behaviors.”

Finally, it showed that L. reuteri modulated stress hormones in a time-of-day-specific manner.

Source: Cell Metabolism

2024, doi: 10.1016/j.cmet.2024.10.003

“Gut microbiota regulates stress responsivity via the circadian system.”

Authors: G.S.S. Tofani et al.