Key Points
- The composition and diversity of the gut microbiome is associated with sleep quality and duration in animal models and humans.
- Peptides released from bacterial peptidoglycan during growth interact with receptors in the brain to trigger sleep-associated responses.
- Other microbial metabolites, such as butyrate and those linked to melatonin synthesis, can directly or indirectly influence sleep.
- Understanding the microbial mechanisms of sleep regulation can inform strategies to improve sleep via the microbiome.
Sleep is a hot commodity-we want it, we need it, but most of us aren't getting enough of it.
Factors like stress, jet lag, work, diet and screen time all interfere with our ability to get the 7-9 hours of solid slumber needed to recover from the physiological pummels of the day.
But there's more to this story than travel and cellphones. How much sleep we get, and its quality, may have ties to "bed bugs" of a microbial variety.
"Sleep is very personal," said John Cryan, Ph.D., professor and Chair of the Department of Anatomy & Neuroscience at the University College Cork. "Some people get by on less; some people get a bit more. Is that due to the composition of [their] microbiome?"
Microbes Impact Sleep-And Vice Versa
Sleep is required to consolidate memories, regenerate tissue and build up energy for emotional regulation and alertness during the day. Sleep deprivation disrupts these processes, increases stress and predisposes people to heart, psychiatric and neurological problems.
We may have some control over how our sleep plays out, but many pieces of the puzzle-particularly those at the cellular level-are out of our hands. Some of them, in fact, are in our guts.
Studies in animal models and humans suggest there is a bidirectional relationship between the composition of the gut microbiota and sleep quality and duration. In mice, altering the gut microbial community, such as through antibiotic treatment, can lead to poorer, more fragmented sleep.
Indeed, a more diverse microbiome is generally correlated with increased sleep efficiency and total sleep time. Better sleep is also associated with a higher abundance of bacteria with health-promoting metabolic functions, like production of short-chain fatty acids (SCFAs), whereas conditions like insomnia are linked with lower abundances of these microbes. Whether insomnia causes these alterations, or vice versa, is still unclear-likely, they feed into one another.
Like many of the chemicals and processes powering our bodies, the composition of the microbiome naturally fluctuates throughout the day. These changes are linked to host circadian processes, and alterations in sleep (e.g., jet lag) can disrupt microbiota rhythms, resulting in important health implications.
"[What] we find in stress-related disorders, [and] in many mental health disorders in general, is that they're often associated with disordered sleep and dysregulation of sleep and circadian rhythms. And so, it's always been a niggle of mine to try to understand how that works," said Cryan.
His lab recently showed in animal models that daily fluctuations in stress pathways closely linked to sleep (e.g., cortisol levels) are modulated by the microbiome. "We're finding that there are circuits in the brain that are sensitive to microbial signals," he shared. Now, researchers are seeking to identify the mechanisms that underlie those sensitivities.
How Microbes Regulate Sleep
For Erika English, a Ph.D. student in the lab of prominent sleep researcher James Krueger, Ph.D., in the College of Veterinary Medicine at Washington State University, the answer to how microbes regulate sleep partly depends on research that began over 100 years ago. At that time, scientists "were actively exploring how you could collect [cerebrospinal] fluid from sleep deprived animals and inject it into a normal, healthy control animal, and they would fall asleep or become very sleepy," she said. This inspired investigations into what substances in the fluid were responsible for this effect. One such compound, known as Factor S, was identified in the 1970s.
But what exactly was Factor S? Krueger and his collaborators were determined to find out. They purified and characterized the compound from sleep-deprived animal brains and liters of human urine (a "catch all" for small molecules in the body). The result: Factor S was a muramyl peptide-a component of peptidoglycan shed by bacteria as they grow and divide. Notably, mammals cannot make muramyl peptides, meaning their presence and observed sleep-inducing qualities originate from bacteria.
Research over the years has shown that these microbial peptides enter circulation from gut bacteria and surpass the blood-brain-barrier, binding to receptors in the brain that trigger sleep-associated responses. English recently discovered that the peptides "fluctuate over the course of the day. They have different levels in different brain areas. If you alter or interrupt normal sleep cycles, those levels change, and the changes are unique depending on the brain area that you are looking at," she explained. These findings suggest there is a regulatory system in the brain guiding the response to bacterial products.
And that response has a lot to do with the immune system. Muramyl peptides spur release of regulatory cytokines (molecules released by immune cells) known to be involved in sleep. This sleep-immune system connection is evident in the context of infection (i.e., being sick makes one tired), but cytokines also appear to underly daily sleep regulation by way of the gut-brain axis.
Sleep at the Cellular Level
While sleep depends on big brain activity, English pointed to a curious observation: if you disrupt brain regions integral to the sleep-wake cycle in animal models, and then treat them with muramyl peptides, they still get sleepy.
These findings challenge the idea that sleep is not solely a global process controlled by complex brain circuits. It is also a local phenomenon initiated at the cellular level.
After periods of intense use, small, local cell groups in the brain "go to sleep," meaning some areas of the brain can enter a sleep state (characterized by slower electrical activity and sleep-like patterns of cytokine secretion) while others remain awake. Global sleep occurs when these disparate local sleep/wake cycles synchronize.
"We have this 2-process model of sleep, [and] we now know that there are separate neuronal regulatory systems: 1 linking sleep to an animal's niche (classical sleep regulatory circuits), and the other circuits that are sensitive to microbial products and secrete somnogenic [sleep-inducing] cytokines," English noted. "Microbes actually give us a way to connect those 2 elements of sleep regulation that have, up until this point, been separate."
If sleep is complex and dynamic, then so are the ways microbes affect it. In addition to muramyl peptides, gut microbes produce and release gobs of molecules every day. Some, like butyrate and metabolites linked to melatonin synthesis, can directly or indirectly influence sleep. Building out the repertoire of known microbial metabolites (and their producers) involved in sleep, as well as the host cellular mechanisms responsible for detecting and responding to them, is a primary priority in the field. Bacteria have and will continue to be an important focus, though Cryan underscored the importance of widening the lens to include phages, archaea and other types of microbes inhabiting our guts as well.
Using Microbes to Enhance Sleep
For many scientists, the goal of such research is to use the discoveries to inform microbe-based strategies for improving sleep. "My hope is that the more we can define and describe the mechanisms that are involved in the microbe-gut-brain access and linked to sleep and circadian rhythms, [the more] this will expand [our ability to develop] some novel treatment and therapeutics for sleep disorders," English said.
There are data suggesting that certain probiotic species (e.g., Lactobacillus and Bifidobacterium) are associated with an altered microbial metabolic profile and improve sleep quality. One study found that adults who received Bifidobacterium animalis subsp. lactis for 8 weeks had better sleep quality, as measured via a widely-used self-reported questionnaire, compared to placebo. Cryan's team demonstrated in a study with 20 college students that those who took a probiotic Bifidobacterium strain in the 8 stressful weeks leading up to an exam reported better sleep than those who received placebo, further highlighting the intersection between gut microbes, stress and sleep.
Prebiotics and dietary changes that directly or indirectly impact sleep are another possible avenue. Are there specific foods (e.g., those rich in tryptophan) that someone can eat at specific times of day to shape their gut microbial menagerie for optimal sleep? Possibly, though research has yet to catch up to this idea of a "chrono prescription for the microbiome," as Cryan puts it.
While less accessible (and appealing), a few small studies have also shown that fecal microbiota transplants may improve sleep in people suffering from chronic insomnia, highlighting a potential modality for improving sleep in certain circumstances.
Still, most trials assessing the effects of microbiota interventions on sleep are small and need further validation before they can have broad translational impact. Sleep is also complicated-microbes are not the sole solution to poor sleep, but one of many internal and external influences on our snoozing quality.
"Along with diet and exercise, sleep is the other part of that trifecta that is really important for our overall wellbeing and our way of navigating the world," Cryan said. "What I'd like to see is that we can enhance wellbeing and potentially mental health by understanding microbiome sleep-interactions."
There is accumulating evidence supporting the relationship between the human gut microbiome and organ function outside the gut. Learn more about gut microbiome communication via the gut-organ axis.
