Feeding immunity: The regulation of circadian immune responses by mealtimes

Both, mice and humans have a striking circadian variability in the responsiveness to innate immune stimuli and in mice, susceptibility to sepsis induced by acute stimulation of the immune system with LPS; and disruption of the circadian rhythm is associated with inflammatory diseases, such as cancer and obesity. The intrinsic cellular clock exists in immune cells and can control some aspects of innate immunity, but what extrinsic signals, termed ‘zeitgebers’ or time-givers, entrain the circadian behavior of immune response are not known. We have investigated the relative contributions of light and the feeding cycle to innate immune responses by dissociating the light cycle and access to food through time restricted feeding (TRF), allowing access to food either during the dark - and natural feeding time of mice - or the light phase. Using RNA profiling we found that the circadian clock in the liver is entirely programmed by food, whereas in the spleen, mainly light influences the expression of clock genes. Strikingly, in this setting susceptibility to LPS-induced morbidity was entrained by the food, not the light cycle, suggesting that food is the ‘zeitgeber’ for circadian susceptibility to LPS-induced sepsis. While the exact mechanism is under thorough investigation, daily mortality patterns following LPS stimulation could not be attributed to corticosteroids or ketone bodies, both of which possess anti-inflammatory properties and exhibit strong food dependency. Understanding the interface between nutrition and circadian rhythmicity may provide new insights with which to design strategies to prevent and improve metabolic and inflammatory diseases in individuals at risk.