The circadian rhythm governs more than just waking and sleeping. The intricate functions of the digestive system rely on the ticking, clock-like rhythm as well. And when a normal day/night, wake/sleep schedule is thrown off track, fatigue is the least of the body’s problems. Disruption of this cycle has negative implications for how the digestive system keeps intestinal infection, cancer, and other gastrointestinal diseases at bay.
A new study linking circadian rhythm and digestive function puts the spotlight on type 3 innate lymphoid cells (ILC3), which rely on circadian rhythm to successfully manage regular function in the intestines. Essentially, ILC3s play moderator between massive populations of healthy gut bacteria and innate intestinal cells.
ILC3s also produce immune molecules that foster a friendly working relationship between the intestinal immune system, healthy gut bacteria, and harmless food particles (potential allergens) while still effectively arming itself against pathogenic bacteria and viruses that may enter the body through the digestive tract.
For the study researchers, what sparked the current investigation was the noticeably high activity of certain “clock genes” (like protein REV-ERB alpha) observed in ILC3s. Even more, immune molecule production by ILC3s occurred in coordination with “clock gene” activity, indicating a connection between ILC3 and circadian rhythm.
"If ILC3 cells are attuned to circadian rhythms, they can anticipate when nutrition is going to arrive in the intestine, which is also when dangerous bacteria might accidentally be consumed and arrive in the gut, too," explained first author Qianli Wang. "For optimal functioning, the gut needs to be prepared for these daily rhythms, and these cells play a pivotal role in that process."
To test the connection, Wang and the others first studied ILC3s extracted from mouse intestines every six hours, looking for the ways “clock gene” activity ebbed and flowed with the natural circadian rhythm. They found that both the genetic activity and immune molecules produced by ILC3s “varied in a predictable pattern” throughout the day.
A second test involved mimicking the wake/sleep schedule of a shift worker in mice. Researchers saw malfunctioning ILC3 cells and lower levels of immune molecule production upon stimulation with infection.
Lastly, researchers created “knock-out” mice to investigate the effect of a missing “clock gene.” These mice were genetically altered to lack “clock protein” REV-ERB alpha. Healthy mice could handle a bacterial infection (Clostridium difficile), but the knock-out mice failed to produce adequate ILC3 cells, and the cells they did manage to produce emitted more of a harmful immune molecule than their normal protective immune molecules. Infection ensued.
The study’s scientists anticipate, based on the current study’s findings, the potential to target “clock genes” to affect immune cells and address adverse health outcomes that occur as a result of the dysfunctional sleep patterns that accompany shift work.
For example, a 2010 study showed that nurses in rotating shift work were linked to abdominal pain and irritable bowel syndrome (IBS) development. While not identifying the direct cause, the researchers did express that the disease states were “independent of sleep quality,” indicating it was other aspects of a disrupted circadian rhythm that could be causing the connection.
"What we've found here is that circadian rhythms directly affect the function of immune cells in the gut, which could help explain some of the health issues we see, such as inflammatory bowel disease and metabolic syndrome,” explained senior author Marco Colonna, MD.