Role of clock genes in gastrointestinal motility

Abstract

Biological rhythms coordinate the timing of our internal bodily functions. Colonic motility follows a rhythm as well: most people will have a bowel movement in the morning and rarely during the night. Recent work provides a potential mechanism for this observation: the mouse colon possesses a functional circadian clock as well as a subset of rhythmically expressed genes that may directly impact on colonic motility. Furthermore, measures of colonic motility such as the colonic tissue contractile response to acetylcholine, stool output, and intracolonic pressure changes vary as a function of the time of day, but these variations are attenuated in mice with disrupted clock function. These laboratory findings are supported by clinical observations. Gastrointestinal symptoms such as diarrhea or constipation are prevalent among shift workers and time-zone travelers, both of which are conditions associated with disruptions in biological rhythms. This review will discuss new insights into the role of clock genes in colonic motility and their potential clinical relevance.

Fig. 1.

Simplified presentation of the circadian-feedback loops. The cycle starts with the formation of a CLOCK/BMAL heterodimer that initiates the transcription of the per-, cry-, rora-, and rev-Erbα genes. PER and CRY proteins subsequently inhibit CLOCK/BMAL1 transcription (loop 1), REV-ERBα inhibits Bmal transcription, whereas RORA activates Bmal transcription (loop 2).

Fig. 2.

Expression and function of colonic clock genes. A: longitudinal muscle myenteric plexus (LMMP) of the mouse colon using double-labeling immunohistochemical staining of neurofilament (red) with PER2 (green) in the mouse colon. Overlap represents superimposition of fluorescent images. B: cross section of human colon showing PER2 immunoreactivity (IR) within ganglia of the myenteric plexus and within the epithelial cells. C: rhythmic per2-luciferase activity in a LMMP preparations from mouse colon maintained in constant darkness for a total of 5 days without medium changes. Although the oscillations dampened after 4 days, this dampening is more likely to represent a dampening due to decreased availability of the substrate luciferin.

Fig. 3.

Conceptual model for circadian regulation of colonic motility. The rhythmic expression of clock genes within the neurons of the myenteric plexus modulate colonic motility through direct or indirect clock-controlled transcription of genes such as acetylcholine (ACh) transferase and neuronal nitrix oxide synthase (nNOS). Direct clock-controlled transcription can be mediated through an E-box element (the consensus sequence for the E-box element is CANNTG) through which clock genes can enhance transcription of downstream gene. Transcription of ACh and nNOS will lead to the rhythmic release of ACh and nitric oxide (NO), which will initiate diverse biochemical, cellular, and physiological processes within the colonic circular muscle, which may in turn, through a cascade of second order messengers and various signaling pathways lead to enhanced colonic motility and, eventually, a bowel movement (BM) at one time of the day and decreased colonic motility at another time of day.