Abstract
Disruptions to circadian rhythm in mice and humans have been associated with an increased risk of obesity and metabolic syndrome. The gut microbiota is known to be essential for the maintenance of circadian rhythm in the host suggesting a role for microbe-host interactions in the regulation of the peripheral circadian clock. Previous work suggested a role for gut bacterial bile salt hydrolase (BSH) activity in the regulation of host circadian gene expression. Here we demonstrate that unconjugated bile acids, known to be generated through the BSH activity of the gut microbiota, are potentially chronobiological regulators of host circadian gene expression. We utilised a synchronised Caco-2 epithelial colorectal cell model and demonstrated that unconjugated bile acids, but not the equivalent tauro-conjugated bile salts, enhance the expression levels of genes involved in circadian rhythm. In addition oral administration of mice with unconjugated bile acids significantly altered expression levels of circadian clock genes in the ileum and colon as well as the liver with significant changes to expression of hepatic regulators of circadian rhythm (including Dbp) and associated genes (Per2, Per3 and Cry2). The data demonstrate a potential mechanism for microbe-host crosstalk that significantly impacts upon host circadian gene expression.
Highlights
All organisms have an autonomous biological clock with an oscillation cycle of approximately 24 hours that temporally regulates daily physiological events
We recently demonstrated that elevated microbial bile salt hydrolase (BSH) expression in the murine GI tract significantly increases local and systemic levels of unconjugated bile acids with profound effects upon lipid signalling pathways, weight gain and cholesterol levels in the host [13,14]
We demonstrate that bile acids generated through microbial activity in the gut are potentially chronobiological signals that influence the circadian clock both locally in the gut, and in the liver (Fig 5)
Summary
All organisms have an autonomous biological clock with an oscillation cycle of approximately 24 hours that temporally regulates daily physiological events. In humans this circadian clock regulates sleep-wake cycles, body temperature and energy metabolism [1]. The central clock in turn influences circadian cycles in PLOS ONE | DOI:10.1371/journal.pone.0167319. Unconjugated Bile Acids Influence Expression of Circadian Genes peripheral tissues through neuronal and hormonal signals (the peripheral clock). The duration of oscillation is not precisely 24 hours, so the central biological clock uses external environmental cues (mainly light and dark cycles) to reset and entrain circadian rhythms [2]
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