© Silke Kiessling
The body clock regulates behaviour and physiology in a circadian (24-h) manner. Circadian disruption, as occurs in shift workers, is associated with gastrointestinal (GI) pathologies, including Inflammatory Bowel Disease (IBD).
The intestinal epithelial cells, key regulators of barrier function and immune homeostasis, harbour a clock which may play a major role in maintaining intestinal homeostasis. In addition, the majority of the gut microbiome, including microbial metabolites, show circadian rhythmicity in both mice and humans. It remains to be addressed whether changes in microbial composition and function are regulated by the intestinal clock and influence GI diseases. Thus, we aim to test whether (i) arrhythmic microbial composition and function in IBD is caused by intestinal clock dysfunction, (ii) lost rhythmicity in microbial metabolites promotes IBD and (iii) IBD pathogenesis can be modulated by restoring circadian microbial metabolite production.
We have determined microbial composition by 16S amplicon sequencing and functioning by targeted and untargeted metabolomics of IBD-relevant mice and mice lacking the intestinal clock, which are prone to develop IBD. We found loss of microbial rhythmicity during IBD, including with respect to bile acid (BA) producers. Accordingly, the rhythmic BA production observed in wild-type mice was arrhythmic in the IBD-relevant mice. Currently we are investigating the impact of time-restricted feeding and timed oral metabolite administration on the progression of IBD.
Results will indicate whether the intestinal clock may become a future target to treat the pathology of IBD in humans. Prevention strategies aimed at improving circadian rhythms of the microbiome in populations at risk, such as shift workers, could then be initiated.
Up until October we will determine the impact of diets and meal timing on microbial rhythmicity. Thereafter we will focus on strategies to restore circadian microbial functioning in IBD.