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How the gut microbiome controls daily metabolic rhythms

New research has clarified how the microbes in the gut (i.e., the gut microbiome) regulate mice’s daily metabolic rhythms, affecting weight gain and metabolic health. An organism’s metabolism changes in response to the cycle of day and night, and this “circadian rhythm” is associated with sleeping and feeding cycles. Some of these metabolic changes are regulated via modification to a cell’s histones, the protein “spools” around which DNA is wound. Depending on histones’ chemical modifications, they may allow or block access to genes, effectively turning specific genes on or off. Since the gut microbiome has also been linked to daily metabolic cycles, researchers asked if the microbiome uses host histone modification to control cyclic gene activity in the gut. To answer this question, the scientists studied histone modifications in the small intestines of either normal or “germ-free” mice that lack all microorganisms. They found that histone modifications in germ-free mice’s intestinal cells did not cycle daily as they did in normal mice. To study how the microbiome was causing this difference in histone modification, researchers surveyed the proteins, called histone deacetylases, which cause many of these modifications. The scientists identified one histone deacetylase in mice, HDAC3, that was not as abundant in germ-free mice as in normal mice and that, like the histone modifications, cycled differently in the presence or absence of a microbiome. Upon further study, researchers confirmed that the microbiome was required for HDAC3’s recruitment to histones at target genes, suggesting that the microbiome was affecting HDAC3 activity. Studying a mouse model with an intact microbiome but without HDAC3 in its intestinal cells gave further clues to HDAC3’s importance: a lack of HDAC3 resulted in disruptions in the daily activity cycles of over 2,700 genes in the intestinal lining. Taken together, these findings demonstrated that the microbiome controls HDAC3 activity to produce wide-reaching effects on the body. For example, many of HDAC3’s target genes in the intestinal lining are involved in nutrient transport and metabolism. Furthermore, researchers discovered that HDAC3 controlled how intestinal cells took up nutrients during digestion, ultimately affecting the concentrations of metabolic products and lipids in the mice’s blood. Because of these effects on nutrient uptake, the researchers also investigated HDAC3’s role in diet-related obesity. They found that HDAC3 in the intestinal lining was required for the microbiome to promote obesity and other negative metabolic effects when mice were put on a high-fat diet. They even found that HDAC3 was important in weight gain induced by experimental jet lag, demonstrating another link between circadian rhythm, the microbiome, and obesity. Overall, these findings highlight a possible way in which the gut microbiome’s regulation of its host’s metabolism has significant impacts on metabolic health. Although future research is needed to determine if the microbiome and HDAC3 play similar roles in people, these experiments have identified possible new targets for the treatment of metabolic disease.

Kuang Z, Wang Y, Li Y,…Hooper LV. The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3. Science 365: 1428-1434, 2019.