Impacts of night shifts on gut- Scramble Brain’s Control of Immune Cell Clock Genes to Impact on Gut Health
People who do night shifts or who travel across time zones very frequently are more likely to become overweight. They also suffer from gut inflammations. There has been considerable research study aimed at trying to understand the impacts of night shifts on the gut and also the underlying mechanisms which link the brain’s circadian clock, that acts in response to the daylight cycle, with physiological processes.
The studies conducted in mice by scientists at the Champalimaud Centre for the Unknown in Lisbon have recently discovered that the functioning of a group of immune cells known to be a strong contributor to gut health is directly controlled by the brain’s circadian clock. This may at least in part explains the link between sleep patterns and gut inflammatory responses. Henrique Veiga-Fernandes, Ph.D., said that the sleep deprivation, or altered sleep habits, will have dramatic health consequences that result in a range of diseases which frequently have an immune component, such as bowel inflammatory conditions. To understand why this happens, the research team started by asking whether immune cells in the gut are influenced
by the circadian clock. The team reported their study findings in Nature, in a paper titled, “Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis.”Nearly all our body cells have genetic mechanisms for following the circadian rhythm. The clock genes do act as their informal name suggests. They effectively inform cells of the time of day, which helps organs and body systems keep to the daily rhythm and anticipate a time of day-related events, such as when it’s time to eat or to sleep. The circadian rhythms rely on local and systemic cues to coordinate mammalian physiology. These are genetically encoded by molecular clocks that allow organisms to anticipate and adapt to extrinsic environmental change, the investigators stated.
Our cell clocks are autonomous, but these still need to be synchronized to make sure that “everyone is on the same page.” As Veiga-Fernandes explained, the cells inside our body don’t have direct information about external light, which means that individual cell clock can be off. The function of the brain’s clock, that receives direct information about daylight, is to synchronize all of these little cell clocks inside the body so that all systems are in synch. And this is absolutely crucial for our wellbeing.
The Type 3 innate lymphoid cells (ILC3s) are a key type of immune cells in the intestine. These cells can fulfill important functions in the gut: they fight infection, control the integrity of the gut epithelium, and instruct lipid absorption, said Veiga-Fernandes. These type of immune system cells have also been shown to interact with neuronal cells, hinting at the possibility that Type 3 innate lymphoid cells function may be affected by changes in circadian rhythms. Type 3 innate lymphoid cells have been shown to be part of discrete mucosal neuroimmune cell units, raising the hypothesis that Type 3 innate lymphoid cells may also integrate systemic neuroimmune circuits to regulate tissues integrity and organismic homeostasis.
Research team’s tests in mice showed that Type 3 innate lymphoid cells were particularly susceptible to having their body clock genes disrupted, whereas other types of immune cell in the intestine weren’t greatly affected. When the team disrupted their clocks, they found that the number of Type 3 innate lymphoid cells in the gut was significantly reduced. These resulted in severe inflammation, breaching of the gut barrier, and also in the increased fat accumulation, he added.
Further studies on this indicated that disruption to the brain’s circadian clock influenced the gene expression in Type 3 innate lymphoid cells, and the cells lost what the research team describes as “postcode receptors.” These tests showed that to be able to localize to the intestine, Type 3 innate lymphoid cells needed to express these cell surface postcode receptors, which acted as tags to instruct the Type 3 innate lymphoid cells—which are transient residents in the gut—where to migrate. Without the brain’s circadian inputs, Type 3 innate lymphoid cells failed to express the tag, which affected their localization.
Researchers found that light cues are major extrinsic entraining cues of Type 3 innate lymphoid cells circadian rhythms, and surgically or genetically induced deregulation of brain rhythmicity resulted in altered Type 3 innate lymphoid cells regulation. In turn, the Type 3 innate lymphoid cells-intrinsic circadian machinery controlled the gut receptor postcode of Type 3 innate lymphoid cells, shaping enteric Type 3 innate lymphoid cells and host homeostasis.
Veiga-Fernandes said that the study results are particularly exciting because they help in clarifying why gut health might become compromised in people who are routinely active during the night. And this mechanism is a beautiful example of evolutionary adaptation, he added. During the day’s active period, the brain’s circadian clock reduces the activity of Type 3 innate lymphoid cells in order to promote a healthy lipid metabolism. But then, the gut could be damaged during feeding. Then after the feeding period is over, the brain’s circadian clock instructs Type 3 innate lymphoid cells to come back into the gut, where they are now needed to fight against invaders and promote regeneration of the epithelium.
Veiga-Fernandes said that people who work at night can suffer from various inflammatory intestinal disorder. It has all to do with the fact that the specific neuroimmune axis is well regulated by the brain’s clock. Any changes in our habits can have an immediate impact on these important, ancient immune cells of the brain.
The regulation of Type 3 innate lymphoid cells activity by systemic circadian circuits may have evolved to maximize metabolic homeostasis, gut defense, as well as an efficient symbiosis with commensal organisms that have been evolutionary partners of mammals. The current data also contributes to a better understanding of how circadian disruptions in our human bodies are associated with metabolic diseases, bowel inflammatory conditions, and also cancer.
The new study results on impacts of night shifts on the gut, add to previous discoveries by the Veiga Fernandes lab linking the immune and nervous systems. The concepts that the nervous system can coordinate the function of the immune system is entirely novel, he added.
