The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3

Circadian rhythmicity is a defining feature of mammalian metabolism that synchronizes metabolic processes to day-night light cycles. Here, we show that the intestinal microbiota programs diurnal metabolic rhythms in the mouse small intestine through histone deacetylase 3 (HDAC3). The microbiota induced expression of intestinal epithelial HDAC3, which was recruited rhythmically to chromatin and produced synchronized diurnal oscillations in histone acetylation, metabolic gene expression, and nutrient uptake. HDAC3 also functioned non-canonically to coactivate estrogen related receptor a (ERRa), inducing microbiota-dependent rhythmic transcription of the lipid transporter gene Cd36 and promoting lipid absorption and diet-induced obesity. Our findings reveal that HDAC3 integrates microbial and circadian cues to regulate diurnal metabolic rhythms, and pinpoint a key mechanism by which the microbiota controls host metabolism. Overall design: 1. RNAseq analysis of epithelial cell transcripts in Germ-free WT mice and conventional HDAC3fl/fl and HDAC3?IEC mice at 4 time points across a circadian cycle. Laser captured epithelial cells from 3 mice were pooled together for RNAseq at each time point. 2. ChIPseq analysis of epithelial cell H3K9ac and H3K27ac in Germ-free and conventional WT mice and conventional HDAC3fl/fl and HDAC3?IEC mice across a circadian cycle. Epithelial cells from 3 mice were pooled together for ChIPseq at each time point. 3. 16s sequencing analysis of fecal bacterial composition in HDAC3fl/fl and HDAC3?IEC mice before and after switching from chow diet to high-fat diet.