Time-Restricted Feeding Alters the Innate Immune Response to Bacterial Endotoxin

Abstract

An important entraining signal for the endogenous circadian clock, independent of light, is food intake. The circadian and immune systems are linked; forced desynchrony of the circadian clock via nighttime light exposure or genetic ablation of core clock components impairs immune function. The timing of food intake affects various aspects of the circadian clock, but its effects on immune function are unknown. We tested the hypothesis that temporal desynchrony of food intake alters innate immune responses. Adult male Swiss Webster mice were provided with food during the night, the day, or ad libitum for 4 wk, followed by administration of LPS prior to the onset of either the active phase (zeitgeber time [ZT]12: Experiment 1) or the inactive phase (ZT0: Experiment 2). Three hours after LPS administration, blood was collected, and serum was tested for bacteria-killing capacity against , as a functional assay of immune function. Additionally, cytokine expression was examined in the serum (protein), spleen, and hypothalamus (mRNA). Day-fed mice suppressed bacteria-killing capacity and serum cytokine responses to LPS during the active phase (ZT12). Night-fed mice increased bactericidal capacity, as well as serum and hypothalamic mRNA responses of certain proinflammatory cytokines during the active phase. Only day-fed mice enhanced serum cytokine responses when LPS challenge occurred during the inactive phase (ZT0); this did not result in enhanced bactericidal capacity. These data suggest that mistimed feeding has functional relevance for immune function and provide further evidence for the integration of the circadian, metabolic, and immune systems.

Training the Circadian Clock, Clocking the Drugs, and Drugging the Clock to Prevent, Manage, and Treat Chronic Diseases

“…Recently TRE has also been shown to improve brain health in Huntington's disease [60]and reduce inflammation from an acute infection. Both studies were performed in mice [61]. Although numerous benefits of TRF have been documented, most of the rigorous studies are in pre-clinical animal models and a few human studies are preliminary pilot or feasibility studies [62,63].…”

Beneficial Effects of Decreased Meal Frequency on Nutrient Utilization, Secretion of Luteinizing Hormone and Ovarian Follicular Development in Gilts

“…Furthermore, decreased MF change the diurnal dynamics and even shift the gut microbiome which had bene ts for metabolic health [10,11]. Decreasing the MF was able to alter the nutrient utilization, and in ammation status in growing pigs [9,12]. The above evidence indicated that meal frequency may play a critical role on the female reproductive system since a body of experimental evidence have indicated a fundamental link between metabolic status and normal estrus cycle.…”

“…Currently, the replacement gilts are typically fed ad libitum, which encourages extending the period of daily nutrient intake and thereby shortening the fasting period. However, growing evidence revealed that this free eating pattern has been associated with an increased prevalence of metabolic diseases in human and rodents [6][7][8], and on the contrary, studies of laboratory animals and human have shown that decreased meal frequency (MF) can increase insulin sensitivity and thereby reduce the obesity related metabolic diseases, and even extend lifespan [7][8][9]. Furthermore, decreased MF change the diurnal dynamics and even shift the gut microbiome which had bene ts for metabolic health [10,11].…”

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“…47 Atypical feeding times also led to worse cytokine expression in mice exposed to bacterial endotoxin, suggesting that mistimed feeding leads to immune system dysfunction. 48 Mistimed feeding leads to uncoupling of the peripheral and master clock genes, which leads to a heightened inflammatory response, as demonstrated by increased levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and higher mortality. 49 In humans, continuous feeding potentiates insulin resistance, hyperglycemia, hepatic inflammation, and impaired bowel function.…”