While many of us prefer the sound of silence, others feel the need to inject a little rhythm into their everyday lives; but how do you do it? Spinning a few records at home, moving to the beat at Samba lessons, or do you use the microorganism-mediated activity of Hdac3 in your gut?! While researchers led by Lora V. Hooper (University of Texas Southwestern Medical Center, Dallas, USA) have kept rather quiet regarding their musical tastes, they have been more forthcoming with regards to their study showing how mouse gut microorganisms use Hdac3 to synchronize metabolism with the body’s daily cycles!
By assessing microbe-laden (“conventional”) and germ-free mice via RNA-seq and ChiP-seq, Kuang et al. established that gut microorganisms mediate normal daily metabolic cycling by regulating the rhythmic activity of the Hdac3 histone deacetylase in small intestine epithelial cells (IECs). This rhythmic activity drives intestinal metabolic gene expression oscillations and controls nutrient uptake.
Overall, these funky new findings may explain why a higher likelihood for human obesity is associated with antibiotic damage and jet lag/nightshift work; so, let’s get down and boogie with all the greatest hits from this pulsating new study:
- The mouse gut microbiome controls daily rhythms in histone acetylation in IECs
- ChIP-seq analysis of IECs from normal mice revealed daily oscillations in H3K9ac and H3K27ac levels at genes involved in metabolic processes
- A similar analysis in germ-free mice found no oscillations and, instead, generally higher acetylation levels at previously oscillating regions
- The mouse gut microbiome promotes histone acetylation rhythmicity through the HDAC3 activity
- While Hdac1 and Hdac3 mRNA display high expression in IECs, Hdac3 displays specifically lower levels in germ-free mice
- However, Hdac3 mRNA levels fail to display oscillation in conventional mice, and instead, histone acetylation rhythmicity involves recruiting HDAC3 to specific genes via the activity of the nuclear receptor co-repressor (NCoR) and components of the circadian clock
- Analyses in mice with Hdac3-null IECs suggest that the microbiota-circadian clock interaction mediated by HDAC3 enhances nutrient uptake in the small intestine and controls intestinal lipid absorption by controlling metabolic gene expression
- However, the authors provide evidence that this interaction also enables high fat diet-induced obesity (likely by enhancing intestinal lipid absorption), while the interruption of this interaction (via antibiotic treatments and circadian disruptions) can worsen metabolic disease
- Interestingly, microbiome-stimulated gene regulation via HDAC3 acts through both canonical and non-canonical pathways
- The elevated expression of metabolic genes in Hdac3-null IECs suggests that HDAC3 functions canonically as a co-repressor through histone deacetylation and suppressed gene expression
- However, the reduced expression of specific metabolic genes in Hdac3-null IECs also suggests an indirect or non-canonical coactivating
- Fascinatingly, the authors demonstrate that HDAC3 functions as a coactivator of estrogen-related receptor a (ERRa)-mediated gene expression
Overall, this new study suggests that Hdac3 integrates microbial and circadian cues to regulate daily metabolic rhythms and pinpoints a key mechanism by which the gut microbiome controls host metabolism. What a fresh and funky finding!
“This regulatory interaction probably didn’t evolve to make us obese, but when combined with today’s calorie-rich diets, obesity arises,” says lead author Hooper, adding that this is speculation and the team is still working to understand all the components of the pathway.
“Our results also suggest that disrupting the interactions between the microbiota and the body’s clock could make us more likely to become obese. These disruptions happen frequently in modern life when we take antibiotics, work overnight shifts, or travel internationally. But we think that our findings might eventually lead to new treatments for obesity – and possibly malnutrition – by altering the bacteria in our guts.”
For more funky findings and rhythmic scientific ruminations, see Science, September 2019.