What causes us to fall asleep? The answer may lie not only in our brains, but also in their complex interaction with the microorganisms that live in our intestines. New research from Washington State University suggests a new paradigm for understanding sleep, showing that a substance found in the mesh-like walls of bacteria, known as peptidoglycan, occurs naturally in the brains of mice and is closely linked to the sleep cycle.

These findings serve to update a broader hypothesis that has been developed at WSU for years—namely, that sleep arises from communication between the body’s sleep-regulating systems and the numerous microbes that live within us. “This has added a new dimension to our previous findings,” said Erika English, a doctoral student at WSU and lead author of two recently published scientific articles presenting the findings.

Sleep as a Result of the Interaction Between the Body and its Microorganisms

This view that sleep arises from this “holobiont state” is part of a growing body of evidence suggesting that our gut microbiome plays an important role in cognition, appetite, sex drive, and other activities — a view that turns traditional brain-centered models of cognition on its head and has implications for our understanding of evolution and free will, as well as the development of future treatments for sleep disorders.

Recent findings on peptidoglycan (PG) support this hypothesis and suggest a possible regulatory role for bacterial cell wall products in sleep. PG is known to promote sleep when injected into animals, but until recently it was assumed that it did not enter the brain naturally. English found that PG, along with its receptor molecules involved in PG signaling and communication, was present at various sites in the brain, with concentrations varying depending on the time of day and sleep deprivation.

The results were published in July in Frontiers in Neuroscience; longtime sleep researcher and WSU Regents Professor James Krueger co-authored the article. English is also the lead author of a recent article co-authored with Krueger in the journal Sleep Medicine Reviews, which presents the “holobiont state” hypothesis of sleep. This article brings together two prevailing views. One assumes that sleep is regulated by the brain and neurological systems. The other focuses on “local sleep,” which views slumber as the result of an accumulation of sleep-like states in small cellular networks throughout the body. Such sleep-like states have been observed in cells in vitro, known as the “sleep in a dish” model.

When these smaller sleep phases accumulate, like when the lights go out in a house, the body tips from wakefulness into sleep. The new hypothesis unites these theories and suggests that sleep is the result of the interaction between the body and its microorganisms—two autonomous systems that interact and overlap. “It’s not one or the other, it’s both. They have to work together,” English said. “Sleep is really a process. It occurs at different speeds for different levels of cell and tissue organization and is the result of comprehensive coordination.”

Sleep Patterns and the Function of the Gut Microbiome

Connections between the microbiome and behavior are emerging on several fronts, suggesting that microorganisms formed in the gut play an important role in cognition and basic human behaviors. This work turns the traditional view of human neurology on its head, suggesting that it is not entirely top-down—i.e., the result of decision-making processes in the brain—but bottom-up—i.e., driven by tiny organisms whose evolution has made animals their hosts and whose needs influence the activities and cognition of their hosts.

“We have an entire community of microbes living inside us. These microbes have a much longer evolutionary history than any mammal, bird, or insect—much longer, billions of years longer,” said Krueger, who was named a “living legend of sleep research” by the Sleep Research Society in 2023. “We believe that the evolution of sleep began eons ago with the activity/inactivity cycle of bacteria and that the molecules that drove that cycle are related to those that drive cognition today.”

English’s work builds on known links between bacteria and sleep, including the fact that sleep patterns influence the function of the gut microbiome and that bacterial infections cause people to sleep more. The new findings raise questions that English would like to pursue further. “Now that the world has recognized how important microbes are not only for disease but also for health, it’s a very exciting time to expand our understanding of how we communicate with our microbes and how our microbes communicate with us,” she said.