Disrupt the circadian clock, and metabolism will change. Alter the microbiome and, again, metabolism will change. Would altering the circadian clock affect the microbiome?
Dr. Derek O’Neil, a postdoctoral fellow in obstetrics and gynecology at Baylor College of Medicine took on the project to answer this question and he found the first evidence that a liver gene in mice has the ability to link the circadian system, the microbiome and the mouse metabolism under dietary restrictions. What is surprising is that it does so in a sex-specific fashion.
Disrupting the circadian clock in mouse liver alters the gut microbiome
Working on the lab of Dr. Kjersti Aagaard at Baylor, O’Neill and his colleagues investigated the connection between the circadian clock and the microbiome by genetically engineering mice to lack – only in the liver – the Npas2 gene which is involved in the circadian rhythm. Then, they determined the effect of lacking the gene on a traditional test for circadian genes. In the test, called restricted feeding, normal feeding hours were disrupted. Instead of having access to unrestricted amounts of food for 12 hours at night (the normal feeding time for mice), the mice had access to food for four hours during the day.
Two groups of mice went through the restricted feeding test for 17 days, the mice lacking the Npas2 gene and normal mice. Before, during and after the test, the researchers took stool samples where they determined the type of microbes present and measured how much food the animals ate and how much they weighted.
The results showed that altering the circadian clock in the liver results in changes in the gut microbiome; the mice lacking the Npas2 gene had microbial communities in their stools that were different than those in normal mice.
In addition, even though both groups of mice ate about the same amount of nutritionally balanced food and lost weight during the restricted feeding test, the mice lacking the Nasp2 gene lost less weight than the normal mice.
“Lacking a gene in the liver that drives the circadian clock was sufficient to not only change the resiliency of these mice to weight loss during restricted feeding but also to change their gut microbiome,” said Aagaard.
“Interestingly, we observed this effect only on the male mice. This is the first scientific mechanistic study that shows clear evidence of a complex interplay between the host circadian system, the microbiome and the host metabolism when under dietary stress.”
The study has potential implications in the clinic. “We speculate that our findings may lead to solutions for people who are resistant to losing weight with restricted feeding as well as the opposite situation,” Aagaard said. “If we manipulated the microbiome, could we see lesser or more weight loss by just changing the time of feeding? Our study could also be applied to situations in which we don’t want to see weight loss, such as cancer patients receiving chemotherapy or during times in life when sleep patterns are turned upside down.”
Closer to their field of interest, pregnancy and neonatal life, the researchers further speculate that their findings may lead to more studies aimed at better understanding the intricate interactions between major disturbances of the circadian clock for both mother and child during neonatal life (when newborns are still learning day from night), the microbiome and preserving the mother’s weight and metabolism.
Would you like to learn more about this study? Find it in the American Journal of Obstetrics and Gynecology.
Dr. Kjersti Aagaard is the Henry and Emma Meyer Chair in Obstetrics & Gynecology and a professor of molecular and human genetics and of molecular and cell biology at Baylor College of Medicine.
Other authors of this work include Christopher J. Stewart, Derrick M. Chu, Danielle M. Goodspeed, Pablo J. González-Rodríguez and Cynthia D. Shope, all from Baylor College of Medicine.
This study was partially supported by the National Institutes of Health grants 1RO1DK089201-01A, R24DK090964-06, T32GM088129 and T32GM07526-37.