Research Article

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

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Science  27 Sep 2019:
Vol. 365, Issue 6460, pp. 1428-1434
DOI: 10.1126/science.aaw3134

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Microbial entrainment of metabolism

The metabolism of mammals is synchronized to daily cycles relating to sleep and mealtimes. It is not surprising that the gut microbiota, which aids in digestion, should also display daily cycling. Kuang et al. found that the gut microbiota can mediate daily cycles epigenetically (see the Perspective by Bishehsari and Keshavarzian). The microbiota induces rhythmic expression of histone deacetylase 3 (HDAC3) in epithelial cells of the small intestine, but not those of the colon. HDAC3 expression drives oscillations in intestinal metabolic gene expression, especially for nutrient transport and lipid metabolism. HDAC3 also directly activates estrogen-related receptor α, which promotes lipid absorption. Consequently, mice that lack a gut microbiota lack daily regulation of their metabolism and become obese on high-fat chow. Disruption of HDAC3 cycling could be an explanation for human obesity associated with antibiotic damage to the microbiota and with sleep disruption caused by jet lag and nighttime working.

Science, this issue p. 1428; see also p. 1379

Abstract

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 noncanonically to coactivate estrogen-related receptor α, 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 for regulation of diurnal metabolic rhythms and pinpoint a key mechanism by which the microbiota controls host metabolism.

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