When the lights dim, the world quiets, and stars track their way across the sky, sleep works its magic. The brain’s sleep centers act as an ever-watchful sentinel, orchestrating an eclipse of consciousness that awakens organ restoration at the cellular and molecular level. Adequate sleep is crucial for maintaining one’s wellbeing. Sleep quantity and quality affect every moment of wakefulness, from brain function to gut health.
“Poor sleep is associated with gut disease like inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), even colon cancer, but we don't know how sleep disruption affects the gut,” said Zhengquan Yu, a molecular biologist at the China Agricultural University who recently collaborated with a team of researchers from multiple universities to explore the underlying mechanism of this phenomenon.
The team studied how sleep deprivation affects gut repair mechanisms in mice and recently reported their findings in Cell Stem Cell.1 They described a novel biochemical cascade that involves aberrant signals from the brain’s sleep centers that are relayed to the gut via the vagus nerve. The study provides critical insight into the underlying mechanism of the connection between sleep disruption and gastrointestinal issues.
Sleep Disruption Impairs Gut Function
The gut interacts with the brain along a two-way communication hub known as the gut-brain axis that transfers information through the vagus nerve and various hormonal and immune signals.2,3 Among such signals are those related to sleep and stress. Sleep supports repair of the intestinal lining, which is continuously shed and replenished by local stem cells. Scientists are increasingly interested in understanding the vagus nerve’s involvement in sleep and how signals exchanged along the gut-brain axis influence gut repair and rejuvenation.
Maksim Plikus, a developmental and cell biology researcher at the University of California, Irvine and coauthor of this study, described the impetus behind this work. “Sleep deprivation [causes] dysfunctional brain activity that seems to translate to peripheral organs. Since the vagus nerve connects the brain to peripheral organs, it [may act] as the delivery system of aberrant sleep patterns, affecting [organ] function and leading to pathology,” Plikus said. “It’s an enticing idea that the health of our vital organs is connected to our sleep. If that’s the case, perhaps treating some of the major diseases of vital organs with improved sleep or anything that mediates it, could be clinically [relevant].”
While mice are nocturnal creatures, they experience sleep deprivation as an acute stressor, much like humans. In their new study, Plikus, Yu, and their teams deprived mice of sleep for two days. Using various biomolecular techniques, they found marked changes in the mice’s intestinal structure, particularly in the activity of stem cells responsible for renewing the gut lining. Overactivity of the vagus nerve increased acetylcholine followed by serotonin in the gut. The resulting oxidative stress undermined normal gene expression in gut stem cells and hindered gut lining regeneration. “Two days of sleep deprivation in mice reduced the number of intestinal stem cells by nearly half. I think it's very striking, because you could see how quickly and severely sleep disruption impairs the gut,” Yu said.
More than the Sum of Parts
Arthur Beyder, a gastroenterologist and biomedical engineer at Mayo Clinic who was not involved in this study, was impressed by the technical and mechanistic aspects of the work. “It’s fascinating and one of a few studies that makes these kinds of mechanistic links,” he said. “IBD and other [gut] disorders are linked to poor sleep. I'm really interested in the broader implications of these kinds of connections.”
Beyder noted the need for additional research to contextualize the clinical relevance of the study, including moving beyond mouse models to human models such as gut organoids, as well as considering the pleiotropic role of serotonin in the body.4 He described that in the routine clinical use of serotonin receptor agonist drugs in patients with gastrointestinal disorders, those individuals respond well to increased serotonin. “I think caution is required to translate a [serotonin-based] mechanism of stem cell disruption [exclusively]. When you get into things like sleep, there are so many different systems involved,” he said. “It would be interesting to see if there is also some connection to circulatory dysfunction because serotonin is critical to maintain blood pressure and other things.”
Shiri Gur-Cohen, a stem cell biologist at the University of California, San Diego who was not involved in this work, praised the authors for the elegant way in which they demonstrated the signaling mechanisms along the gut-brain axis, including gut stem cell involvement. “The idea that the brain-gut connection is also encrypted within the stem cells themselves and how they are receiving those signals on a systemic level is absolutely fascinating,” she said.
As researchers increasingly integrate a niche-specific view of the body with a more systemic approach, the elegance of local and distant communication between organs becomes more apparent. When it comes to sleep deprivation, bone-tired exhaustion may be more than just a feeling—its cellular and molecular effects are far reaching.
- Zhang M, et al. Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction. Cell Stem Cell. 2026;33(2):306-324.e8.
- Aburto MR, Cryan JF. Gastrointestinal and brain barriers: Unlocking gates of communication across the microbiota-gut-brain axis. Nat Rev Gastroenterol Hepatol. 2024;21(4):222-247.
- Bonaz B, et al. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci. 2018;12:49.
- de Hoyos-Vega JM, et al. Modeling gut neuro-epithelial connections in a novel microfluidic device. Microsyst Nanoeng. 2023;9:144.
