Sleepless nights compromise gut health, study says

The function of a group of immune cells known to be strong contributors to gut health are directly controlled by the brain's circadian clock, according to new findings published in the journal Nature.

It is well known that individuals who work nightshifts, or travel often across different time zones, have a higher tendency to become overweight and suffer from gut inflammation. The underlying cause for this robust phenomenon has been the subject of many studies that tried to relate physiological processes with the activity of the brain's circadian clock, which is generated in response to the daylight cycle.

The current study, led by Henrique Veiga-Fernandes, PhD, at the Champalimaud Centre for the Unknown in Lisbon, Portugal, found that sleep deprivation, or altered sleep habits, can have dramatic health consequences, resulting in a range of diseases that frequently have an immune component, such as bowel inflammatory conditions.

Almost all cells in the body have an internal genetic machinery that follows the circadian rhythm through the expression of what are commonly known as "clock genes". The clock genes work like little clocks that inform cells of the time of day and thereby help the organs and systems that the cells make up together, anticipate what is going to happen, for instance if it's time to eat or sleep.

Even though these cell clocks are autonomous, they need to be synchronized. The cells inside the body don't have direct information about external light, which means that individual cell clocks can be off, according to Veiga-Fernandes.

"The job of the brain's clock, which receives direct information about daylight, is to synchronize all of these little clocks inside the body so that all systems are in synch, which is absolutely crucial for our wellbeing,” he said in a statement.

Among the variety of immune cells that are present in the intestine, the team discovered that Type 3 Innate Lymphoid Cells (ILC3s) were particularly susceptible to perturbations of their clock genes.

"These cells fulfill important functions in the gut: they fight infection, control the integrity of the gut epithelium and instruct lipid absorption,” said Veiga-Fernandes. "When we disrupted their clocks, we found that the number of ILC3s in the gut was significantly reduced. This resulted in severe inflammation, breaching of the gut barrier, and increased fat accumulation."

These results drove the team to investigate why is the number of ILC3s in the gut affected so strongly by the brain's circadian clock. When the team analyzed how disrupting the brain's circadian clock influenced the expression of different genes in ILC3s, they found that the molecular zip code was missing. They found that, to localize to the intestine, ILC3s need to express a protein on their membrane that works as a molecular zip-code. This tag instructs ILC3s, which are transient residents in the gut, where to migrate. In the absence of the brain's circadian inputs, ILC3s failed to express this tag, which meant they were unable to reach their destination.

According to Veiga-Fernandes, these results are very exciting, because they clarify why gut health becomes compromised in individuals who are routinely active during the night.

"This mechanism is a beautiful example of evolutionary adaptation,” said Veiga-Fernandes. "During the day's active period, which is when you feed, the brain's circadian clock reduces the activity of ILC3s in order to promote healthy lipid metabolism. But then, the gut could be damaged during feeding. So, after the feeding period is over, the brain's circadian clock instructs ILC3s to come back into the gut, where they are now needed to fight against invaders and promote regeneration of the epithelium."

It comes as no surprise then that people who work at night can suffer from inflammatory intestinal disorders, said Veiga-Fernandes.

“It has all to do with the fact that this specific neuro-immune axis is so well-regulated by the brain's clock that any changes in our habits have an immediate impact on these important, ancient immune cells,” he said.

This study joins a series of groundbreaking discoveries produced by Veiga-Fernandes and his team, all drawing new links between the immune and nervous systems.

"The concept that the nervous system can coordinate the function of the immune system is entirely novel,” he said. “It has been a very inspiring journey. The more we learn about this link, the more we understand how important it is for our wellbeing and we are looking forward to seeing what we will find next.”