Summary: Study reveals the function of specific immune cells, well documented as playing a significant role in gut health, is directly controlled by our circadian clock.
Source: Champalimaud Center for the Unknown
It is well known that individuals who work night-shifts, 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.
Now, the group of Henrique Veiga-Fernandes, at the Champalimaud Centre for the Unknown in Lisbon, Portugal, discovered that the function of a group of immune cells, which are known to be strong contributors to gut health, is directly controlled by the brain’s circadian clock. Their findings were published today in the scientific journal Nature.
“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”, says Veiga-Fernandes, the principal investigator who led the study. “To understand why this happens, we started by asking whether immune cells in the gut are influenced by the circadian clock.”
The big clock and the little clock
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 still need to be synchronised in order to make sure that “everyone is on the same page”. “The cells inside the body don’t have direct information about external light, which means that individual cell clocks can be off”, Veiga-Fernandes explains. “The job of the brain’s clock, which receives direct information about daylight, is to synchronise all of these little clocks inside the body so that all systems are in synch, which is absolutely crucial for our wellbeing”.
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”, explains 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 robust results drove the team to investigate why is the number of ILC3s in the gut affected so strongly by the brain’s circadian clock. The answer to this question ended up being the missing link they were searching for.
It’s all about being in the right place at the right time
When the team analysed how disrupting the brain’s circadian clock influenced the expression of different genes in ILC3s, they found that it resulted in a very specific problem: the molecular zip-code was missing! It so happens that in order to localise 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”, says 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”, he continues, “that people who work at night can suffer from inflammatory intestinal disorders. 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.”
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. 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”, he concludes.
Light-entrained and brain-tuned circadian circuits regulate ILC3 and gut homeostasis
Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism1. ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence2,3. Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut ‘postcode receptors’ of ILC3s. Strikingly, light–dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.