Key to the riddle of sleep may be linked to bacteria | WSU Insider | Washington State University
For an astonishing example of co-evolution — not just involving two organisms but a whole host that have co-evolved over millions of years — you need look no further than your own body, as a paper in *Frontiers in Neuroscience* by Erika L. English and James M. Krueger of Washington State University (WSU) shows. It reports the finding that sleep may be a co-evolved condition in which gut micro-organisms play a central role.
The researchers showed that, in mice, there is a close relationship between sleep patterns and the cyclical presence in the brain of a substance known as peptidoglycan (PG), normally found in the mesh-like walls of gut bacteria. Although co-evolutionary relationships are a well-established concept in evolutionary biology, this example illustrates just how intimate such relationships can become — to the point where it is difficult to say, in biological terms, which organism is the “product” of the other. To what extent are we the product of our gut bacteria, and to what extent are they the product of us?
Of course, creationism has nothing to say about this kind of co-evolution because the Bible is silent on the matter of micro-organisms or evolution. It contains nothing that wasn’t visible to its Bronze Age authors with the naked eye, or that lived outside the narrow confines of their limited experience. It was written by people with no appreciation of the history of life on Earth or of how it has been shaped by environmental change and ecological balances over deep time.
Co-evolution and Why Creationism Fails to Explain It. What is co-evolution?The discovery by the Washington State researchers is explained in an article by Shawn Vestal in *WSU Insider*.
- Co-evolution occurs when two or more species exert evolutionary pressures on each other, leading to reciprocal adaptations.
- Classic examples include:
- Flowers and pollinators.
- Predators and prey.
- Hosts and parasites.
- The new research suggests something even deeper: sleep itself may be partly a product of our long evolutionary partnership with gut microbes.
Why creationism has no answer:
- The Bible was written in an age when microbes were unknown, so it says nothing about them or their roles in health and behaviour.
- Creationism cannot explain reciprocal adaptations or ecological balances developing over millions of years.
- Evolutionary biology, by contrast, not only explains co-evolution but uses it to make testable predictions — such as expecting gut microbes to influence other fundamental processes.
Key to the riddle of sleep may be linked to bacteria
What causes us to sleep? The answer may lie not only in our brains, but in their complex interplay with the micro-organisms spawned in our intestines.
New research from Washington State University suggests a new paradigm in understanding sleep, demonstrating that a substance in the mesh-like walls of bacteria, known as peptidoglycan, is naturally present in the brains of mice and closely aligned with the sleep cycle.
Those findings serve to update a broader hypothesis that has been in development at WSU for years — proposing that sleep arises from communication between the body’s sleep regulatory systems and the multitude of microbes living inside us.
This added a new dimension to what we already know.
Erika English, lead author
School of Molecular Biosciences
Washington State University
Pullman, WA, USA.
This view of sleep as arising from that “holobiont condition” joins a growing body of evidence suggesting that our gut microbiomes play an important role in cognition, appetite, sex drive and other activity — a view that turns traditional brain-centric models of cognition upside-down and has implications for our understanding of evolution and free will, as well as the development of future treatments for sleep disorders.
The recent findings regarding peptidoglycan, or PG, lend weight to that hypothesis and point to a possible regulatory role for bacterial cell wall products in sleep. PG is known to promote sleep when injected in animals, but until recently, the conventional view held that it did not naturally migrate to the brain.
English found that PG, along with its receptor molecules involved in PG signaling and communication, was present in different locations within the brain, at levels that changed with the time of day and sleep deprivation.
The findings were reported in July in Frontiers in Neuroscience; longtime WSU sleep researcher and Regents Professor James Krueger co-authored the paper. English is also lead author of a recent paper with Krueger in the journal Sleep Medicine Reviews that proposes the “holobiont condition” hypothesis of sleep.
That paper combines two prevailing views. One posits that sleep is regulated by the brain and neurological systems. Another focuses on “local sleep,” which frames slumber as the result of an accumulation of sleep-like states among small cellular networks throughout the body. Such sleep-like states have been observed among cells in vitro, known as the “sleep in a dish” model.
As these smaller pockets of sleep accumulate, like lights going off in a house, the body tips from wakefulness toward sleep.
The new hypothesis merges those theories, proposing that sleep results from the interplay between the body and its resident micro-organisms — two autonomous systems that interact and overlap.
It’s not one or the other, it’s both. They have to work together. Sleep really is a process. It happens at many different speeds for different levels of cellular and tissue organization and it comes about because of extensive coordination.
Erika English.
Sleep really is a process. It happens at many different speeds for different levels of cellular and tissue organization and it comes about because of extensive coordination.
Links between the microbiome and behavior are emerging on several fronts, indicating that micro-organisms formed in the gut play an important role in cognition and fundamental human behaviors. This work upends the traditional view of human neurology, suggesting that it is not completely top-down — i.e., the result of decision-making in the brain — but bottom-up — i.e., driven by the tiny organisms whose evolution shaped animals to serve as their hosts and whose needs influence the activities and cognition of their hosts.
We have a whole community of microbes living within us. Those microbes have a much longer evolutionary history than any mammal, bird or insect — much longer, billions of years longer. We think sleep evolution began eons ago with the activity/inactivity cycle of bacteria, and the molecules that were driving that are related to the ones driving cognition today.
Professor James Krueger, co-author
Integrative Physiology and Neuroscience
Washington State University, Pullman, WA, USA.
[Professor Krueger] was named a “Living Legend in Sleep Research” by the Sleep Research Society in 2023.
English’s work expands upon known links between bacteria and sleep, including the fact that sleep patterns affect the function of the gut microbiome and that bacterial infections cause people to sleep more.
The new findings begin to delve into questions that English looks forward to exploring further.
Now that the world has come to appreciate how important microbes are, not just for disease but also for health, it’s a very exciting time to start to expand on our understanding of how we are communicating with our microbes and how our microbes are communicating with us
Erika English.
Publication:
Sleep-inducing bacterial cell wall components isolated from brain and urine of sleep deprived animals were identified as peptidoglycan (PG) and muropeptides in the 1980s. Following host detection of PG/muropeptides, downstream signaling mechanisms include release of effector molecules, e.g., cytokines involved in sleep regulation. Understanding of physiological brain PG changes has remained limited, in part due to the historic difficulties of PG quantitation. Herein, we report murine brain PG levels in multiple brain areas within the context of animals’ rest-wake cycles and after sleep loss. Significant time-of-day changes in brain PG levels occurred in all brain areas; lowest levels occurred during the transition from rest to wake periods, at zeitgeber time 12 (ZT12). Highest levels of PG were in brainstem while olfactory bulb, hypothalamic, and cortical PG levels were lower. After 3 h of sleep disruption, PG levels increased in the somatosensory cortex, but decreased in brainstem, and hypothalamus. After 6 h of sleep disruption, PG increased in the brainstem and olfactory bulb compared to control levels. Further, RNA-seq analyses of somatosensory cortical tissue was used to assess sleep loss-dependent changes in genes previously linked to PG. Multiple PG-related genes had altered expression with sleep loss including PG binding and signaling molecules, e.g., Pglyrp1 and Nfil3. In summary, brain PG levels were dependent on time of day, brain area, and sleep history. Further, sleep loss altered brain gene expression for PG-linked genes. Collectively, these data are consistent with the hypothesis that microbe-host symbiotic interactions are involved in murine sleep regulatory mechanisms.This work by English and Krueger underscores just how interdependent life truly is. We are not self-contained organisms but ecosystems, shaped by millions of years of interaction with the microbes that live within us. Far from being passive passengers, these microbes actively influence some of our most fundamental biological processes — even sleep.
Introduction
In 1982, somnogenic muramyl peptides (MPs), components of bacterial cell wall peptidoglycan (PG), were posited to be involved in sleep regulation (Krueger et al., 1982a). Subsequently, sleep and microbes were linked in many ways (Besedovsky et al., 2019; Imeri and Opp, 2009), e.g., sleep loss results in bacteremia (Everson and Toth, 2000), and bacterial infections profoundly alter sleep (Toth and Krueger, 1988). Host sleep patterns affect the composition and function of the gut microbiome (Voigt et al., 2016; Benedict et al., 2016.1; Poroyko et al., 2016.2; Bowers et al., 2020; Withrow et al., 2021) and gut dysbiosis occurs with sleep loss and sleep pathologies (Wang et al., 2022; Poroyko et al., 2016.2). Recently, PGs have gained attention as having important roles in brain and additional behaviors, e.g., anxiety-like behavior (Arentsen et al., 2018), brain development (Arentsen et al., 2017), thermoregulation (Gabanyi et al., 2022.1), and feeding (Gabanyi et al., 2022.1), yet a mechanistic understanding of microbe-host dynamics and characterization of the molecules involved requires assessment of brain area changes in PG associated with physiological variation. Both sleep and gut microbiome dynamics display circadian fluctuations (Voigt et al., 2016; Heddes et al., 2022.2; Yan et al., 2021.1), however, until recently, a role for microbes in physiological sleep regulation seemed unlikely. This is despite extensive characterization of PG and the structural requirements of its smaller MP building blocks as sleep promoting compounds (Krueger et al., 1982.1b; Krueger et al., 1984). Thus, heretofore whether spontaneous changes in brain PG levels occurred with sleep physiology remained unknown. Furthermore, although the brain expression of a PG binding protein, now called Pglyrp1, increases during rat (Rehman et al., 2001) and mouse (Oles et al., 2020.1) sleep loss, little is known of other PG-linked mRNA species changes after sleep loss; herein several cortical changes are described.
English, Erika L. ; Krueger, James M.
Bacterial peptidoglycan levels have brain area, time of day, and sleep loss-induced fluctuations Frontiers in Neuroscience (2025) 19 DOI: 10.3389/fnins.2025.1608302
Copyright: © 2025 The authors.
Published by Frontiers Media S.A. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
This discovery also highlights the predictive power of evolutionary theory. Once we recognise that humans and their microbiome have co-evolved, it becomes reasonable to expect that microbes might play key roles in regulating processes traditionally thought of as “purely human”. That expectation is now being borne out by research.
For creationism, however, such findings are simply invisible. A worldview that denies evolution cannot explain why bacteria should so intricately regulate a universal behaviour like sleep, nor why those relationships extend across species. Science, by contrast, not only explains the patterns we see but opens up new avenues for research into health, disease, and the very nature of life.
In the end, discoveries like this remind us that humans are not apart from the rest of life, but part of a vast, interdependent web. To understand ourselves, we must also understand the billions of unseen organisms that help shape who — and what — we are.
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