Why are people with unregulated hours, such as night workers, more prone to intestinal inflammation and obesity? A now-discovered relationship between immune function and the brain's circadian clock could provide the answer to this question.
It is well known that people who work night shifts, or who frequently change time zones, are more likely to be overweight and more often suffer from intestinal inflammation.
Many studies have tried to unravel the cause of this phenomenon, trying to relate the physiological processes with the activity of the brain's circadian clock, which is generated in response to the night-day cycle.
Now, Henrique Veiga-Fernandes' team, at the Champalimaud Center in Lisbon, has discovered that the function of a certain group of immune cells, known to make a very significant contribution to intestinal health, is under the direct control of the circadian clock. of the brain. Their results were published on September 18th in Nature magazine.
“Sleep deprivation, or poor sleep habits, can have serious effects on health, causing a range of diseases that often have an immune component, such as intestinal inflammation”, says Veiga-Fernandes, the lead researcher who led the study.
"To understand why this happens, we started by wanting to know if intestinal immune cells were influenced by the circadian clock."
big clock, small clocks
Almost every cell in the body has an internal genetic machinery that follows the circadian rhythm through the expression of so-called “clock genes”. These genes work like little clocks that tell cells the time of day, helping the organs and systems they make up to anticipate what is going to happen, for example if it's time to eat or sleep.
As each of these little clocks is autonomous, they need to be synchronized. “Cells inside the body do not receive direct information about the external luminosity, which means that some of them may not be mark the right time”, explains Veiga-Fernandes. "The task of the brain's big clock – which, indeed, receives information directly from daylight – is therefore to synchronize all the small clocks that exist within the body so that all systems are in turn synchronized, which is absolutely crucial for our well-being”.
Among the various immune cells present in the intestine, the team found that so-called "innate lymphoid type 3 cells" (ILC3 for its acronym in English) were particularly sensitive to disturbances in their clock genes. “These cells play important roles in the intestine: they fight infections, control the integrity of the intestinal wall and regulate the absorption of lipids”, explains Veiga-Fernandes.
"Now, when we disturbed their clocks, we found that the number of ILC3 in the intestine significantly decreased, which led to severe inflammation, failure of the intestinal barrier and increased accumulation of fat."
These results led the team to ask why the brain's circadian clock had such a marked effect on the number of ILC3 in the gut. The answer to this question turned out to be the “missing link” they were looking for.
In the right place, at the right time: that's the question
When scientists looked at how the disturbance of the brain's circadian clock affected the expression of several genes in ILC3, they found that it triggered a very specific problem: the molecular “zip code” of these cells disappeared!
It turns out that in order to localize in the gut, ILC3s need to express a protein in their membrane that functions as a molecular zip code.
This marker tells ILC3 that they only reside transiently in the intestine where they should migrate. In the absence of signals coming from the brain's circadian clock, the ILC3s no longer express this marker, meaning they are unable to reach their destination.
According to Veiga-Fernandes, these results are very exciting, as they clarify why intestinal health suffers in people who are regularly active during the night.
“This mechanism is a wonderful example of evolutionary adaptation”, says the researcher. “During the active period of the day, which corresponds to the times we eat, the brain's circadian clock reduces the activity of ILC3 in order to promote a healthy lipid metabolism. But at the same time, the intestine can get damaged during meals. Therefore, once the feeding period is over, the brain's circadian clock tells the ILC3 to return to the intestine, where they are now needed to fight against eventual invaders and promote the regeneration of the intestinal epithelium (wall)”.
“It is therefore not surprising”, continues Veiga-Fernandes, “that people who work at night are susceptible to suffering from inflammatory bowel disorders. It has everything to do with the fact that this specific neuro-immune axis is so well regulated by the brain's clock that any change in our habits has immediate effects on these important primordial cells.”
This study joins a series of fundamental discoveries, made by Veiga-Fernandes and his team, that establish new relationships between the immune and nervous systems.
“The notion that the nervous system is capable of coordinating the function of the immune system is completely new. It has been a very inspiring journey; the more we learn about this relationship, the better we realize how important it is to our well-being. We are now waiting for what we will discover next”, he concludes.
Author Champalimaud Center
Science in the Regional Press – Ciência Viva
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