KSEF RDE: Regulation of Enteric Bacterial Clocks by the Host's Circadian System

Circadian rhythms are fundamental properties of nearly all organisms. The capacity to generate circadian rhythms in gene expression, biochemistry, physiology and behavior is shared by all groups of eukaryotic organisms that have been studied in any detail. Until recently, only one prokaryotic organism has been shown to exhibit a circadian clock, the cyanobacterium Synechococcus elongatus (Cohen SE, Golden SS. Circadian Rhythms in Cyanobacteria. Microbiol Mol Biol Rev. 2015 Dec;79(4):373-85.). However, our laboratory has discovered a gastrointestinal commensal bacterium, Enterobacter aerogenes, that expresses a temperature compensated circadian clock that is synchronized by the hormone melatonin (Paulose JK, Wright JM, Patel AG, Cassone VM. Human Gut Bacteria Are Sensitive to Melatonin and Express Endogenous Circadian Rhythmicity. PLoS One. 2016 Jan11; 11(1): e0146643) and that is entrained by changes in ambient temperature equivalent to the daily changes in body temperature (TB) (Paulose and Cassone, unpublished). This is an extremely important observation that points to a complex “metaorganism” in which circadian oscillators in the brain entrain circadian oscillators in the periphery, such as in intestines, which in turn entrain bacterial circadian clocks. However, current data derive from bacteria in a petri dish; we do not know how these bacterial clocks behave within the host intestines. We propose to determine 1) whether E. aerogenes expresses rhythms in situ by imaging bioluminescent E. aerogenes through the body wall of laboratory mice using an IVIS Imaging System, which is currently in the animal care facilities of the University of Kentucky, 2) whether destruction of the mouse circadian clock by gene knockout or surgical destruction of the brain clock affects bacterial rhythms, and 3) whether administration of the hormone melatonin to the mouse affects the phase or period of bacterial clock. These data will be used as preliminary studies for proposals to the National Institutes of Health.