The circadian rhythms (sleep-wake cycles)—integrated in the suprachiasmatic nuclei in the hypothalamus—can influence a wide range of host physiological functions, ranging from digestion to body temperature.
Although previous data showed that our gut microbiota has its own circadian clocks and may respond to environmental light changes, the impact of circadian cycles on gut homeostasis is poorly understood.
New research led by scientists from Champalimaud Centre for the Unknown (Lisbon), Columbia University (New York), and ULisboa (Lisbon) reveals that neuroimmune pathways controlled by circadian cycles influence intestinal physiology in mice.
Within the gut ecosystem, innate lymphoid cells are a clear example of how neuronal and immune systems communicate to the benefit of host homeostasis. Of these, Group 3 enteric innate lymphoid cells (ILC3s) are involved in regulating inflammation and metabolism by interacting with the gut microbiota and influencing mucosal defense.
Godinho-Silva and colleagues went a step further and sought to explore whether environmental stimulus such as light and brain-derived signals might regulate the function of ILC3s and gut homeostasis in mice.
The researchers found that mature intestinal ILC3s expressed high levels of circadian clock genes Clock, Arntl, Cry1, Nr1d1 and Per1. Moreover, by examining mice with an altered expression of the circadian activator Arntl, it was found that ILC3s had their own autonomous circadian regulation.
In a second step, the authors explored the functional effects of ILC3s’ own circadian signals. The removal of ILC3-intrinsic Arntl in mice led to an altered intestinal homeostasis. That was accompanied by a higher susceptibility to Citrobacter rodentium, changes in the gut microbiota, impaired reactivity of the intestinal epithelium, and a disrupted lipid metabolism.
Altogether, these results show that ILC3 circadian rhythms regulate host gut homeostasis and enteric defense.
Lastly, the researchers explored the factors affecting ILC3 circadian rhythms. The reversal of light-dark cycles had a profound effect on the circadian clocks of enteric ILC3s, which was reported through an inversion of the peak of their circadian cycle. Such ILC3 circadian fluctuations were genetically encoded and were maintained despite exposure to constant darkness.
In contrast, antibiotic-driven changes in the gut microbiota and food access restricted to a 12-hour period had little impact on the physiology of enteric ILC3s.
To further demonstrate the role of circadian-controlled pathways on enteric ILC3s and intestinal physiology, an alteration of the suprachiasmatic nuclei involved in regulating circadian rhythms was provoked through either surgical or genetic induction. This dysregulation altered ILC3 circadian clocks and led to increased fat accumulation and a deregulated gut microbiota.
These findings have characterized how changes in light-dark cycles are processed by a specialized group of immune cells with their own clock machinery. As such, both light stimulus and hypothalamus-derived circadian signals can regulate enteric ILC3s and intestinal homeostasis.
As Veiga-Fernandes stated in a recent Research Highlight in Nature Reviews Gastroenterology & Hepatology: “[Our study] will allow us to uncover whether therapeutic targeting of these neuroimmune axes can be explored in inflammatory and metabolic diseases.”
Godinho-Silva C, Domingues RG, Rendas M, et al. Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis. Nature. 2019. doi: 10.1038/s41586-019-1579-3.
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