A microbiota-epigenetic circuit controls systematic circadian programs in the gut epithelium.

The intestinal microbiota is an important factor that regulates mammalian circadian rhythms and health. We previously reported that the microbiota synchronizes lipid uptake and metabolism in the intestinal epithelium through histone deacetylase 3 (HDAC3). However, the breadth and significance of microbiota-circadian crosstalk in the intestine are not well understood. Here, we show that the gut microbiota programs the rhythmic expression of a broad range of biological processes, and temporally orchestrates epithelial functions and physiology in accordance with the rhythmic gut environment. Protein synthesis, cell proliferation, and metabolic and immune activities are differentially expressed in the daytime and nighttime respectively, indicating a daily alternation of "working" and "recharging" themes in the gut. The rhythms of gene expression are dampened or altered in germ-free mice, suggesting that the microbiota helps to structure the timing of host gene expression. Further analysis showed that HDAC3 drives a vast majority of these microbiota-dependent circadian programs, likely through rhythmic deacetylation of histones. Motif enrichment analysis revealed that HDAC3 could differentially control distinct rhythmic pathways, most likely by recruiting different transcription factors. These findings provide a systematic view of how the commensal microbiota exploits an epigenetic factor to program just-in-time functions in the intestinal epithelium and maintain host homeostasis.