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 α (ERRα), inducing microbiota-dependent rhythmic transcription of the lipid transporter gene Cd36 and promoting lipid absorption and diet-and jet lag-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. One sentence summary The intestinal microbiota induces daily metabolic rhythms and controls lipid uptake through the enzyme histone deacetylase 3.