Circadian rhythms of gastrointestinal function are regulated by both central and peripheral oscillators

Abstract

Circadian clocks are responsible for daily rhythms in a wide array of processes, including gastrointestinal (GI) function. These are vital for normal digestive rhythms and overall health. Previous studies demonstrated circadian clocks within the cells of GI tissue. The present study examines the roles played by the suprachiasmatic nuclei (SCN), master circadian pacemaker for overt circadian rhythms, and the sympathetic nervous system in regulation of circadian GI rhythms in the mouse Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6-hydroxydopamine has no effect on feeding and locomotor rhythmicity in light-dark cycles or constant darkness but attenuates stool weight and stool number rhythms. Again, however, restricted feeding reestablishes rhythms in locomotor activity, feeding, and stool output rhythms. Ex vivo, intestinal tissue from PER2::LUC transgenic mice expresses circadian rhythms of luciferase bioluminescence. Chemical sympathectomy has little effect on these rhythms, but timed administration of the β-adrenergic agonist isoproterenol causes a phase-dependent shift in PERIOD2 expression rhythms. Collectively, the data suggest that the SCN are required to maintain feeding, locomotor, and stool output rhythms during ad libitum conditions, acting at least in part through daily activation of sympathetic activity. Even so, this input is not necessary for entrainment to timed feeding, which may be the province of oscillators within the intestines themselves or other components of the GI system.

Effects of Circadian Disruption on Physiology and Pathology: From Bench to Clinic (and Back)

“…Similar results were found in SCN-ablated mice, where restricted feeding re-established locomotor, feeding, and stool output rhythms (Malloy et al 2012). Per1-2 double knockout mice exhibited abolished rhythms in colonic functions, such as motility, intracolonic pressure changes, stool output, and circular muscle contraction (Hoogerwerf 2010).…”

“…Increased general symptoms for gastrointestinal disorders were more prevalent among shift workers as compared with day workers (Koller 1983), and aircrew members, especially those on long-distance flights, had more upper-GT symptoms than ground staff (Enck et al 1995). The consequences on gastrointestinal functions of shifting working schedules might be related to an increase in food consumption during the rest cycle, since time of feed has been shown to be the strongest Zeitgeber in gastrointestinal oscillators (Malloy et al 2012;Polidarova et al 2011), resulting in a misalignment between circadian clocks among the body. There is a higher prevalence on peptic ulcer among shift workers (Higashi et al 1988;Segawa et al 1987), which might be related to higher incidences in Helicobacter pylori infections in shift workers (Pietroiusti et al 2006;Zober et al 1998).…”

The melatonin-sensitive circadian clock of the enteric bacteriumEnterobacter aerogenes

“…The circadian biological clock figures to play a central role in that process, both from the perspective of circadian regulation of the microbiome by the host's circadian clock and from the perspective that microbiota may influence gastrointestinal (GI) clocks. There is extensive evidence from rodent studies in our laboratory and others [1][2][3][4] that the gastrointestinal system contains a self-sustaining circadian clock capable of regulating circadian patterns of motility, secretion and gene expression. [1][2][3] This clock is coordinated with the light: dark cycle and the circadian clock within the brain's suprachiasmatic nucleus (SCN) via the sympathetic nervous system.…”

“…[1][2][3] This clock is coordinated with the light: dark cycle and the circadian clock within the brain's suprachiasmatic nucleus (SCN) via the sympathetic nervous system. 4 Further, the GI clock can independently entrain to the timing of the presence or absence of food. 1,4 Microbial signaling affects both homeostatic maintenance of intestinal function as well as circadian control of gastrointestinal function.…”

“…4 Further, the GI clock can independently entrain to the timing of the presence or absence of food. 1,4 Microbial signaling affects both homeostatic maintenance of intestinal function as well as circadian control of gastrointestinal function. 5,6 Disruption of the circadian clock, either via dietary restriction or phase shifting (e.g.…”