Gut microbiome responsible for feeling stressed in the morning?

Chronic stress and sleep cycle disturbances are two companions that many of us have in common these days. Meanwhile, our understanding of the gut microbiome influence on our nervous system grows. Stress, disturbed sleep and alterations in microbiome are often observed in stress-related psychiatric disorders, such as anxiety and depression. We also know that the signals concerning stress response, circadian system, and signals originating in the gut microbiome all move using the same pathways (the hypothalamic-pituitary-adrenal, or HPA, axis). Given this body of evidence, a group of scientists led by Gabriel S. S. Tofani in Ireland decided to investigate the role of gut microbiome in the interplay between the stress and circadian systems.

The extensive study, currently in press at Cell Metabolism, used three types of mice: conventional (unaltered microbiome), germ-free (no microbiome), and antibiotic-depleted microbiome. First, they performed shotgun metagenomic sequencing of unaltered mouse gut microbiome at different timepoints in the day to map which bacterial strains show oscillating relative abundance patterns. They also evaluated the diurnal fluctuations in corticosterone (stress hormone) levels and the transcription of circadian system genes. The rhythm of these fluctuations was altered or lost in depleted-microbiome mice. Notably, blood corticosterone levels of depleted-microbiome mice were higher than the other two groups around the sleep-wake transition (see figure below and remember that mice are nocturnal: they wake up at night).

The study then investigated how alterations in microbiome affect stress response pathways at different timepoints in the day. The rhythm of certain gene transcription in hippocampus and amygdala was lost; notably, altering response to glucocorticoid (key component of both circadian and stress systems). The daily patterns of the HPA axis were also altered, pituitary being most affected, which points to it being the source of the corticosterone increase in depleted-microbiome mice.

The changes observed in microbiome-depleted mice manifested in altered stress-sensitive behaviors, depending on time of day. Conventional mice, after acute restraint stress around the sleep-wake transition, showed reduced social interaction (and corresponding increase in blood corticosterone), while microbiome-depleted mice exhibited no changes in behavior (or corticosterone level). Around the wake-sleep timepoint, both types of mice showed a response to stress.

Fecal microbiome transfers were performed to confirm that the observed effects in circadian and stress systems were due to changes in microbiome. The donors were microbiome-depleted and conventional mice, and the microbiome material for transplant was collected either around sleep-wake timepoint (which showed the increased corticosterone peak) and wake-sleep timepoint (when corticosterone level was lowest). The recipients (germ-free mice) experienced an increased corticosterone level after receiving the sleep-wake point transplant, compared to wake-sleep point, regardless of the donor.

Additionally, metagenomic sequencing was performed on the cecal contents of the recipients. Differences in proportions of different bacterial genera were found based on the time of donor material collection and on the donor type (normal vs depleted microbiome). Only one bacteria species (Limosilactobacillus reuteri) increased in recipients that received both microbiome-depleted and conventional transplants collected around the sleep-wake transition. The abundance of L. reuteri undergoes significant diurnal oscillation, with its peak coinciding with corticosterone peak in both conventional and microbiome-depleted mice. Finally, a group of mice received L. reuteri orally either 6 hours before sleep-wake transition or 6 hours before wake-sleep transition. Corticosterone level increase was observed only at sleep-wake transition, indicating that L. reuteri affects its release in a time-of-day-specific manner.

This research underscores the importance of healthy microbiome in maintaining our mental health, especially managing stress. It also demonstrates the potential of probiotic treatments for stress-related disorders, such as anxiety and depression. The deepening of the knowledge in this field and, particularly, the characterization of the exact bacterial strains that could be utilized as treatment could be aided by single-cell sequencing methods. Atrandi Biosciences has developed the semi-permeable capsule (SPC) technology which enables microbial DNA sequencing at single-cell level, allowing to identify strains and perform absolute quantification of species in the sample.

?? Find out more here: Single–Cell Metagenomics | Atrandi.com

Reference

1. Tofani et al. Cell Metab 2024; in press; https://doi.org/10.1016/j.cmet.2024.10.003

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