Unconjugated Bile Acids Influence Expression of Circadian Genes: A Potential Mechanism for Microbe-Host Crosstalk

• Published in: PloS one 2016-12, Vol.11 (12), p.e0167319-e0167319
• Main Authors: Govindarajan, Kalaimathi, MacSharry, John, Casey, Patrick G, Shanahan, Fergus, Joyce, Susan A, Gahan, Cormac G M
• Format: Article
• Language: English
• Subjects: Acids; Animals; Bacteria; Bile; Bile acids; Bile Acids and Salts - metabolism; Bile Acids and Salts - pharmacology; Bile salts; Biological clocks; Biology and Life Sciences; Cell Line, Tumor; Circadian Clocks - genetics; Circadian rhythm; Circadian rhythms; CLOCK Proteins - genetics; Colon; Crosstalk; Cryptochromes; Epithelial Cells; Gastrointestinal Microbiome; Gene expression; Gene Expression Regulation - drug effects; Genes; Health aspects; Host-bacteria relationships; Humans; Hydrolase; Ileum; Intestinal microflora; Liver; Male; Medicine and Health Sciences; Metabolic syndrome; Metabolic syndrome X; Mice; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Models, Biological; Obesity; Oral administration; Organ Specificity - genetics; Period 2 protein; Period 3 protein; Regulators; Research and Analysis Methods; Risk factors; Rodents; Salts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167319

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.