Gut inflammation and other conditions that involve the immune system are more common among people with irregular sleep patterns, including those who work night shifts. Now, new research in mice has uncovered a previously unknown mechanism that could help to explain the connection.
The mechanism concerns group 3 innate lymphoid cells (ILC3s). These immune cells have a strong role in controlling metabolism, inflammation, and other biological processes.
In a recent Nature paper, the scientists explain how they used mice to better understand the role of ILC3s in the gut.
“These cells,” says senior study author Henrique Veiga-Fernandes, Ph.D., “fulfill important functions in the gut — they fight infection, control the integrity of the gut epithelium, and instruct lipid absorption.”
Veiga-Fernandes works at the Champalimaud Centre for the Unknown, in Lisbon, Portugal. He leads a group that investigates communication at the cellular level between the nervous system and the immune system.
“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,” Veiga-Fernandes explains.
Research has shown that people who work shifts are more likely to develop certain long term health problems.
“To understand why this happens,” Veiga-Fernandes continues, “we started by asking whether immune cells in the gut are influenced by the circadian clock.”
He and his colleagues found that ILC3s are particularly sensitive to changes in their clock genes, the genes that control rhythmic cell processes.
They also uncovered a circuit that links the circadian, or 24-hour, clock in the brain to ILC3s in the gut.
It appears that disruptions to this circuit, which senses changes in environmental light, can alter ILC3 clock genes. These genetic changes can impair the immune cells’ ability to regulate gut health.
The team demonstrated this effect by disrupting the 24-hour clock in the mice’s brains.
The authors write that “Surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome, and altered lipid metabolism.”
Nearly all the cells in the body have clock genes that help them to follow a 24-hour cycle.
Clock genes tell cell machinery what the time is so that the body’s biology can prepare for cycle-sensitive activity, such as eating or sleeping.
While each cell’s clock genes can keep the time independently, they rely on the master clock in the brain to keep them synchronized.
In addition, because the brain’s clock circuitry is sensitive to external light, the connection with clock genes in the rest of the body helps to keep body functions in sync with day and night cycles.
The team found that disrupting the ILC3s’ clock genes dramatically reduced their presence in the gut.
“This resulted in severe inflammation, breaching of the gut barrier, and increased fat accumulation,” notes Veiga-Fernandes.
Further investigation revealed the reason for the dramatic drop in ILC3s in the gut. It appears that disruption to the brain’s circadian circuit stops an important signal from reaching the ILC3 clock genes.
Loss of the signal affects a protein that tells the transient ILC3 cells where to migrate to. The protein works like a destination zip code in a satnav, and without the signal from the brain’s circadian circuit, it cannot set up the zip code.
Veiga-Fernandes says that he and his team are very excited by these results because they help to explain why people who are active at nighttime are more likely to have poorer gut health and experience inflammatory illnesses.
He suggests that the body has evolved so that during daylight, when feeding prevails, the circadian clock in the brain tells ILC3s to leave the gut. This reduces ILC3 activity in the gut, which boosts lipid metabolism.
However, reduction in ILC3 activity also leaves the gut vulnerable to damage. So, at night, when feeding does not prevail, the brain’s clock tells the ILC3s to go back into the gut and carry out defensive and repair tasks.
“It [all has] 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.”
Henrique Veiga-Fernandes, Ph.D.