Sleep deprivation harms the gut via the vagus nerve, early study reveals

A night or two of poor sleep can do more than cause tiredness — it may also mess with stem cells in the gut, making the organ susceptible to inflammatory disorders, a mouse study finds.

The new research revealed that sleep deprivation disrupts the function of gut stem cells in ways that could raise the risk of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease.

The study, published Feb. 5 in the journal Cell Stem Cell, described a multicomponent pathway that relays aberrant signals from the sleep center in the brain to the intestinal cells. This haywire signaling reduces the regenerative capacity of the gut lining.

"We now have evidence showing that sleep is not just [important] for the brain but for overall health," Dragana Rogulja, a neuroscientist at Harvard Medical School who was not involved in the study, told Live Science.

Insomnia affects an estimated 10% of adults worldwide. In addition to wreaking havoc on people's daily function, chronic sleep disruptions are linked to an increase in the incidence of numerous chronic conditions, including IBD, diabetes, high blood pressure and major depressive disorder.

Among those with IBD, over 75% report experiencing sleep disturbances. In a study of over 1,200 people whose IBD was in remission, those with impaired sleep had double the risk of relapse, compared with well-rested individuals with the condition. However, most studies of sleep disturbances focus on the brain, so it was largely unknown how these disturbances affect other organs, such as the gut.

To uncover how the sleep-deprived brain influences the bowels, the team focused on intestinal stem cells, which are key players in maintaining gut health — namely, the integrity of the organ's lining. They deprived mice of sleep for two days and observed that their intestines showed signs of oxidative stress. These mice had nearly half the number of stem cells as the guts of well-rested mice, as well as a reduced capacity to regenerate after damage.

"This really showed how quickly and severely sleep disruption damages the gut," study co-author Zhengquan Yu, a molecular biologist at China Agricultural University, told Live Science.

A deeper exploration of the molecular changes taking place in the intestines revealed that sleep deprivation was tied to an increase in serotonin in the mice's guts. Serotonin is crucial for signaling the gut to release digestive fluids and for controlling the muscle contractions that move food through the system. However, prolonged exposure to high serotonin levels can contribute to issues such as diarrhea, IBD and the development of tumors. Thus, tight control of serotonin levels is essential for a healthy gut.

In the mice, a lack of sleep not only caused an excessive amount of serotonin to be released from intestinal cells but also reduced "reuptake" of the molecule — meaning more and more of the chemical messenger built up in the gut. When the team tried injecting serotonin into the guts of well-rested mice, they observed changes that resembled those caused by sleep deprivation.

But exactly how do the brain signals associated with poor sleep reach the gut? Yu and his colleagues speculated that the vagus nerve, which regulates gut-brain communication under stress, could bridge this gap.

To test their theory, the researchers examined the effects of sleep deprivation in mice that had their vagus nerve severed. These animals maintained normal levels of serotonin and a higher number of intestinal stem cells, compared with sleep-deprived mice with intact vagus nerves. Blocking vagus-nerve signals also protected the gut from the effects of disrupted sleep. The researchers also identified the chemical messenger acetylcholine as the main signaling molecule released from the vagus nerve that triggers serotonin release.

"Every component in this cascade is really important as a target for potential therapy," study co-author Maksim Plikus, a cell biologist at the University of California, Irvine, told Live Science. Next, the team wants to study the cascade in miniature models of the gut, called organoids.

"We have to move to human intestinal organoids to start testing conservation of the cell types and the circuitry," Plikus said.

Now, Yu and his team are investigating the relevance of this pathway in the context of chronic sleep disorders to determine if long-term activation of the vagus nerve could contribute to the development of cancer or IBD. Eventually, they aim to develop therapies targeting the vagus nerve or the molecular pathways involved, to treat gut dysfunction in patients with insomnia.

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