Disruption of the Intestinal Clock drives Dysbiosis and Impaired Barrier Function in Colorectal Cancer

The circadian clock governs organismal physiology and homeostasis, and lifestyle factors may contribute to the misalignment of biological rhythms. In particular, timing of food intake and dietary content are robust entrainment cues that regulate circadian rhythms, especially in peripheral tissues. Also, diet and timing of feeding impact the rhythmic composition of the gut microbiome. Therefore, defining how circadian misalignment impacts the gut microbiome is imperative in the context of diseases impacting the intestinal epithelium. In particular, we and others have shown that disruption of the circadian clock drives the progression of colorectal cancer (CRC). However, how the intestinal clock impinges on the microbiome to potentially accelerate CRC pathogenesis is unknown. We utilize an Apc-driven mouse model of CRC where we disrupt the circadian clock in the intestine to investigate the effect on the microbiota and intestinal homeostasis. We identify changes to tight junction gene expression and intestinal permeability upon clock disruption alone that is further exacerbated when combined with a tumor-prone mouse model. Using metagenomics sequencing, we find clock associated changes to bacterial genera including Bacteroides, Parabacteroides and Helicobacter. When clock disruption is combined with cancer development, we find dysregulation of many more genera including Fusobacterium, Paramuribaculum and Megasphaera in addition to Bacteroides. Finally, we identify microbial pathways altered in clock disruption and cancer including upregulation of amino and fatty acid metabolism, and reduced mucus metabolism. Altogether, our findings suggests that clock disruption mediated changes to intestinal permeability and microbiota composition may contribute to CRC pathogenesis.