Latest Research: The Gut Microbiota Influences the Hypothalamic-Pituitary-Adrenal Axis, Disrupting the Circadian Rhythm in Key Stress-Processing Brain Regions

Humans spend approximately one-third of their lives sleeping. However, the fast-paced lifestyle of modern society has led to widespread sleep disorders, such as difficulty falling asleep and frequent nighttime awakenings. Finding effective solutions for insomnia has thus become a significant topic in biological research.

Our body is equipped with two ancient self-regulation mechanisms: the circadian rhythm system and the stress response system. The circadian rhythm helps us adapt our physiological activities to the Earth's natural light-dark cycle, while the stress response system enables rapid reactions to emergencies. Recently, the gut microbiota, often referred to as the "third brain," has garnered widespread attention for its influence on various physiological processes. However, whether these three systems interact—particularly regarding stress-induced insomnia—remains an open question.  

To address this, a research team led by Professor Cryan at University College Cork recently published a study titled "Gut Microbiota Regulates Stress Responsivity via the Circadian System" in Cell Metabolism. The study revealed that the gut microbiota maintains positive feedback for stress responses by regulating the circadian rhythm of the hypothalamic-pituitary-adrenal (HPA) axis. This biological process operates around the clock, spanning 24 hours. These findings not only deepen the understanding of the gut-brain connection but also suggest that maintaining gut health could potentially alleviate stress-related issues like insomnia and other emotional disorders.

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Gut Microbiota Circadian Rhythm Variations Sustain Brain Function  

Previous research has shown that the circadian rhythm variations of gut microbiota are critical for maintaining host metabolic health. But do these variations also impact brain function?

To explore this, researchers performed metagenomic sequencing on the gut microbiota of mice. The results showed that circadian rhythm significantly influenced Lactobacillus species, particularly Lactobacillus reuteri and Lactobacillus johnsonii. These lactobacilli are commonly used as probiotics in yogurt and dietary supplements.

Prior studies have indicated that gut microbiota can modulate stress responses and baseline corticosterone levels via the HPA axis. Building on this, researchers investigated whether circadian rhythm plays a role in this process. The results confirmed that gut microbiota significantly impacts serum corticosterone composition.

To further understand how gut microbiota influences brain function, researchers collected samples from the suprachiasmatic nucleus (SCN), hippocampus, and amygdala of the experimental mice for RNA transcriptome sequencing. The analysis revealed that gut microbiota affects not only central circadian rhythms but also downstream signaling mechanisms that synchronize peripheral and central clocks, thereby influencing brain stress responses in a time-dependent manner.

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Temporal Modulation of Brain Stress Responses by Probiotics  

The limbic system, comprising brain structures evolved from the archicortex and paleocortex, plays a vital role in stress responses. Researchers focused on the circadian rhythm variations in the hippocampus and amygdala transcriptomes.  

Targeted enrichment analysis revealed that the affected genes were predominantly associated with stress responses and glucocorticoid signaling. This suggests that gut microbiota modulates stress responses by influencing the circadian rhythm of stress pathways in key brain regions.

To comprehensively examine the impact of gut microbiota on brain metabolism, researchers employed metabolomics analysis. Results indicated that alterations in gut microbiota led to circadian rhythm changes in glutamate metabolism within the brain, subsequently affecting stress responsiveness.

This groundbreaking research underscores the pivotal role of gut microbiota in addressing mental health challenges. While this concept isn't entirely new, the rigorous experimental evidence compels us to reassess the multifaceted and enduring impact of gut microbiota.

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Gut Microbiota, Stress, and Depression  

Interestingly, stress influences the activity of Brunner's glands in the gut, disrupting microbiota balance and impacting both the brain and immune system.

In biology, structure and function often complement each other. Notably, this study explored not only the biological mechanisms between stress and gut microbiota but also the anatomical structure of the gut. The findings revealed that Brunner's glands in the duodenum are crucial for the proliferation and functionality of lactobacilli, the key probiotics highlighted earlier for their role in mitigating stress responses and regulating circadian rhythm.

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Conclusion  

Stress and insomnia can feel overwhelming and disheartening, but this research offers hope. The findings suggest that supplementing with probiotics, such as Lactobacillus, provides a simple yet effective way to improve sleep quality and resilience to stress. These probiotics not only support gut health but also influence mental state and circadian rhythm through the complex gut-brain axis. For those struggling with stress and insomnia, incorporating probiotic-rich foods like yogurt or other fermented products into the daily diet might be worth a try.

Reference

1. Tofani, Gabriel S S et al. "Gut microbiota regulates stress responsivity via the circadian system." Cell metabolism, S1550-4131(24)00399-1. 2 Nov. 2024, doi:10.1016/j.cmet.2024.10.003