Wrong place, wrong time

How do sleepless nights compromise the health of your gut? A newly found link between the body’s clock and the immune system may very well be the answer.

Immunophysiology Laboratory

A person working late at night feels discomfort in the gut, then sleeps durning the day.

The Question

It is well known that individuals who work night-shifts, or travel often across time zones, have a higher tendency to become overweight and suffer from gut inflammation. However, the underlying cause for this robust phenomenon has been a long-standing mystery. 

What is the biological link between our daily schedules and our intestinal health?

Scientific Approach

To answer this question, the team zoomed in on the body's time-tracking mechanisms. These control our daily rhythm, determining when we wake up, fall asleep, or become hungry. For instance, the digestive system is geared towards breaking up food and absorbing nutrients during the day's active period and shifts to maintenance and repair during sleep.

Since the body's smooth functioning requires that the right thing happens at the right time, almost every cell contains its own "clock". These cell clocks continuously follow a 24-hour cycle.

Day and night pass as we see a running clock over a person and then in the cells.
A person receives light from the outside, this tunes the brain clock which then sends a signal that synchronises cells clocks.

But there's a snag: The cells inside the body don't have direct information about external light. Consequently, just like old-fashioned wrist watches, they can be off. How do the many millions of individual cell clocks get in sync?

Our bodies cleverly overcome this challenge with the help of the "brain clock".

Neurons in this brain structure use direct information about external light from the eyes to track the day-night cycle. The brain clock then sends out signals all across the body, effectively tuning cell clocks everywhere.

So why do reversed schedules cause intestinal problems? The researchers hypothesised that the culprit must be cells in the gut whose function critically depends on time. In particular, the team focused on the cells of the immune system. They reasoned that many of the conditions triggered by reversed schedules have an immune-related component, such as chronic inflammation.

But there are several types of immune cells in the intestine, how did the researchers find out which one was the culprit? 

Searching for day-night cycle dependent immune cells in the gut.
A mouse get the clocks of its ILC3 cells disrupted which creates problems in the gut.

The answer was uncovered with the help of the mouse animal model. Using advanced techniques, the team turned off the clocks of different cell types one at a time. For most cell types, this manipulation had little or no effect on the health of the animals. However,  when the clocks of ILC3 cells (Type 3 Innate Lymphoid Cells) were turned off,  the mice began to suffer from severe inflammation, breaching of the gut barrier and increased fat accumulation. 

These results were very exciting! The team has identified a specific cell type that was sensitive to day-night signals in a way that directly influenced the animals' intestinal health. 

Moreover, when they examined the gut of these animals, they found a dramatic decrease in the numbers of these cells. 

Given that the number of these cells in the gut decreases without a functional cell-clock, the team inferred that light-dark signals must be controlling their location. But how does it work?

The answer to this question ended up being the missing link they were searching for all along. 

Following further experiments, the researchers discovered that brain clock signals instruct the cells to produce a little molecule that works as a location tag, or "zip code". This tag is attached to the surface of each cell. Then, it directs the cell away from its "home base" and into the intestine. When the cells arrive at their destination, they work on fighting infection and repairing the lining of the gut. 

Cells receive a night signal and produce surface tags that direct them to the gut. When day comes the cells leave the gut.
Time passes behind a silhouette of a person whit the brain and gut highlighted.

However, when one's schedule is chronically shifted, the brain clock is exposed to light during the night, which causes it to malfunction. Consequently, the cell clocks also get knocked out of tune, leading the cells to lose their "zip codes". As a result, the cells cannot get to the gut, where negative health consequences quickly ensue.  

This discovery sheds light on the elusive reason why people who have reversed schedules may suffer from intestinal disorders. This particular immune function in the gut is so tightly regulated by the brain's clock that any change in habits has an immediate impact on one's health.

Current status
of the project

The team is investigating how the immune system interacts with other systems in the body while dissecting where and when these interactions happen. Research work examines healthy processes as well as those that occur in diseases such as obesity, cancer and asthma. In the long run, the team aims to study how their findings could help develop novel therapeutic approaches. 

Immunology - Neuroscience - Disease - Fundamental research
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