Regular as clockwork: the role of circadian rhythms in gut inflammation

Abstract

Inflammatory bowel disease is a chronic inflammatory condition that carries significant morbidity. Despite advances in medical therapy, 50% of patients require surgical intervention, highlighting the need for further research to improve medical management of IBD patients. Circadian, 24h rhythms regulate numerous physiological processes including immunity. Circadian rhythms are driven by molecular clocks and aligned by environmental stimuli such as light or food timing. There are growing data to suggest a link between colonic inflammation (colitis) and the circadian clock. This thesis explores the role of the circadian clock in development of intestinal inflammation as well as the influence of intestinal inflammation on local gut clocks and daily rhythmic processes. Data presented here demonstrate that the intestinal circadian landscape is altered in mice exposed to acute dextran sulphate sodium (DSS) colitis. Specifically, inflammation drives circulating leukocytes and subpopulations including regulatory T cells within the lamina propria to oscillate in number through the day, making them attractive targets for chronotherapy. This thesis shows DSS colitis disrupts microbiome rhythmicity in addition to its impact on microbiome composition and diversity. The resident intestinal epithelial cell (IEC) clock, vital for host-microbiome interactions and gut homeostasis, is rapidly disrupted following DSS exposure, however, the IEC clock is not integral to propagation of acute DSS colitis. The thesis progresses to identify an independent role for the IEC clock in regulation of microbiome rhythmicity and composition, which challenges the common view that food timing is the dominant entrainer. Paradoxically, ablation of the IEC clock confers a dysbiotic microbiome but also confers a protective effect on diet-induced obesity in mice fed high-fat diet. Together, these findings demonstrate the range of rhythmic processes affected by inflammation and highlights the importance of understanding the role of the circadian clock in host-microbiome interactions in health, inflammation and metabolic disease.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Mclaughlin (Supervisor) & Julie Gibbs (Supervisor)