How Sleep is Connected to the Brain and Gut

Sleep is one of the most essential human activities — so essential, in fact, that if we don’t get enough sleep for even one night, we may struggle to think, react, and otherwise make it through the day. Yet, despite its importance for function and survival, scientists still don’t fully understand how sleep works.

A single answer is unlikely to explain the function of sleep since processes like cognition, immunity, and metabolism are all sleep dependent⁽¹⁾.

Numerous clinical and experimental research links insufficient sleep with serious health problems⁽²⁾ and sleep restriction has been shown to lead to premature death in model organisms (e.g., dogs, rats, flies)⁽³⁾.

Specifically, what makes sleep required for survival in the most basic sense?

Sleep is generated by neurons and it’s been assumed that death observed with sleep deprivation occurs from impaired brain function. This notion is supported by the significant decrement in cognitive function that occurs following sleep loss⁽⁴⁾.

In addition to impairing cognition, sleep loss leads to dysfunction of the gastrointestinal, immune, metabolic, and circulatory systems⁽⁵⁾.

In humans, chronic inadequate sleep is associated with heart disease, type 2 diabetes, depression, obesity, etc. It’s unclear whether these are secondary consequences of altered nervous system function or direct and independent effects on sleep deprivation.

Sleep & oxidative stress

A proposed necessary function of sleep is prevention of oxidative stress in the brain⁽⁶⁾.

Research indicates altered antioxidant response in the brain during sleep⁽⁷⁾ and recent evidence demonstrated that sleep loss alters the redox (i.e., oxidation-reduction) state of several sleep-regulating neurons in the fly brain, influencing their activity⁽⁸⁾.

Interestingly, the brain does not appear to be significantly damaged by sleep deprivation and others have searched for signs of oxidative stress in other areas.

Reactive oxygen species (ROS) have been identified as unstable, short-lived, and highly reactive molecules – as drivers of cellular damage and lethality during sleep deprivation.  Essentially, ROS triggers widespread oxidation and to gain stability, they interact with macromolecules (DNA, proteins, lipids) and destabilize them⁽⁹⁾.

Recent evidence in animals demonstrated an unexpected, causal link between sleep deprivation and premature death. Evidence indicates that death is always preceded by the accumulation of reactive oxygen species in the gut⁽¹⁰⁾.

Interestingly, when the fruit flies were given antioxidants that neutralized and cleared reactive oxygen species from the gut, sleep-deprived flies remained vibrant and had normal lifespans. These findings indicate that under certain circumstances, animals can survive without sleep.

This opens exciting new avenues of research to fully elucidate the consequences of inadequate sleep and someday may potentially inform the design of new approaches to counteract its detrimental effects in humans.

Compounds with antioxidant properties that were quite effective at clearing reactive oxygen species from the gut are compounds such as melatonin, lipoic acid and NAD.

Fig: Reactive oxygen species are cleared from the gut by the compounds that rescue survival⁽¹⁰⁾.

These findings indicate that if oxidation in the gut can be prevented, it’s possible to offset the effect of losing sleep. As mentioned, this is very important due to the host of diseases that surface when you don’t sleep enough.  

A very recent study found a gene (CCHa1) that when depleted, caused fruit flies to wake very easily. Although this gene is present in both the nervous systems and the gut, flies were aroused more easily only when it was depleted in the gut.

This research also showed that arousal was suppressed when the diet was rich in protein.

Essentially, there is a signaling pathway by which information about ingested proteins is conveyed from the gut to the brain to help suppress arousability. 

Higher protein concentration in the gut influences activity of enteroendocrine cells that release the peptide CCHa1 to increase which is the mechanism behind suppressing arousability⁽¹¹⁾.

This research implies that dietary choices impact sleep quality and this connection in humans can be investigated to comprehend how diet could be manipulated to enhance sleep.

Figure adapted from Titos et al. 2023⁽¹¹⁾

Summary

This work provides an updated framework for thinking about sleep regulation. Sleep consumes the entire body, but traditionally most efforts to comprehend sleep are focused on the nervous system. Recent observations indicate that a more integrative approach is needed to understand some of the biggest mysteries in biology.

The centuries-old idea that digestive and nervous systems are critically linked in normal physiology and disease seems to merit particular attention.

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10.    Vaccaro, A., et al., Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut. Cell, 2020. 181(6): p. 1307-1328 e15.
11.    Titos, I., et al., A gut-secreted peptide suppresses arousability from sleep. Cell, 2023. 186(7): p. 1382-1397 e21.