Understanding the Gut Microbiota’s Influence on Stress and the Brains Circadian System

Researchers at University College Cork have revealed the complex link between the gut microbiota, stress responses and circadian rhythms. This study, published in Cell Metabolism, indicates that depleting gut bacteria alters stress hormone levels and gene expression in the brain, specifically highlighting the timing and patterns of the circadian clock.

The influence of the gut-brain axis on health

The complex network of microorganisms living in our digestive system, known as the gut microbiome, has far-reaching impacts on our health that go well beyond digestion. This community of trillions of bacteria, fungi and other microbes has important roles in immune function, metabolic processes and mood regulation.

One way the gut microbiome exerts its influence is through the gut-brain axis, an intricate communication network that connects the gut and the brain. Through this pathway, gut microbes can send signals that affect brain activity and mental processes, underscoring the deep connection between our digestive and nervous systems. This network has been implicated in several mental health conditions, such as anxiety and depression.

Previous research has highlighted the connection between the hypothalamic-pituitary-adrenal (HPA) axis and the gut microbiome, indicating that microbial composition can impact the body’s response to stress.

Several studies have indicated that the HPA axis is also intertwined with the circadian rhythm – the body’s internal 24-hour clock, which regulates sleep cycles, hormone release and other vital functions.

Although prior research has shown the relationship between gut microbes and brain function, stress responses and circadian rhythms, these studies have mostly examined each effect separately – leaving it unclear how these interactions work together.

The gut microbiota regulates the stress response via the circadian clock

The team used metagenomic sequencing to analyze daily changes in gut microbiota in normal (control) mice and two types of microbiota-depleted mice: antibiotic-treated and germ-free. They also examined how these changes affected the rhythms of corticosterone, a stress hormone, and the activity of circadian genes in key areas of the brain. In particular, they looked at how the gut microbiota influenced the timing and patterns of gene expression related to stress.

The depletion of gut microbiota, either through antibiotics or in germ-free mice, resulted in increased levels of corticosterone and altered patterns in the HPA axis. Gene expression assays showed that the rhythmic expression of stress-related genes in key brain regions – like the hypothalamus, pituitary gland and adrenal gland – was disrupted in microbiota-depleted mice.

Microbial depletion also resulted in the proteins that keep the blood-brain barrier intact, a protective network of blood vessels and cells that separates the brain from the bloodstream, to lose their regular patterns of expression. This may cause the barrier to become more permeable, making it easier for signals from gut microbes to enter the brain.

The mice also showed disrupted behavioral patterns. While control mice showed reduced social interaction during stress, the microbial-depleted mice did not display the same behavior.

The study also highlighted certain gut bacteria, such as Limosilactobacillus reuteri (L. reuteri), as important players in the body's stress response regulated by circadian rhythms. L. reuteri appears to influence the secretion of stress hormones, connecting the natural daily fluctuations of gut microbes to changes in how the body responds to stress.

Designing microbiota-based therapies

“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. These findings underscore the importance of maintaining a healthy microbiome, particularly for those living in today’s stressful and fast-paced environment,” said corresponding author Dr. John Cryan, chair and professor of anatomy at the University College Cork.

As modern lifestyles disrupt circadian rhythms through irregular sleep, high stress and unhealthy diets, this research highlights the crucial role of gut microbiota in supporting the body's natural stress regulation – and may pave the way for potential therapeutic strategies such as psychobiotics.

“Our work also demonstrates that exploring this relationship between the gut microbiota and circadian rhythms will be key in the development of microbiota-based therapies for the stress-related disorders in the future,” said lead author Dr. Gabriel Tofani, post-doctoral researcher at the University College Cork.

“The potential to improve mental health through microbiome-based interventions is very real, and this study takes us one step closer to that goal,” said Dr. Paul Ross, director of APC Microbiome Ireland.

Reference: Tofani GSS, Leigh SJ, Gheorghe CE, et al. Gut microbiota regulates stress responsivity via the circadian system. Cell Metab. 2024. doi: 10.1016/j.cmet.2024.10.003

This article is a rework of a press release issued by University College Cork. Material has been edited for length and content.