Researchers at the Technical University of Munich and the University of Surrey have discovered that infant gut microbiomes have their own circadian rhythm, even when they are cultivated outside of the body. The finding comes from a randomized controlled trial that also demonstrated that diet has less impact on the development and composition of the infant microbiome than previously thought.

Their research is published in Cell Host & Microbe in an article titled, “Diurnal rhythmicity of infant fecal microbiota and metabolites: A randomized controlled interventional trial with infant formula.”

The circadian system drives 24-hour oscillations to control body and organ functions; however, the contribution of circadian rhythms in the developing gut, including the process of microbial colonization, is completely unknown.

“We found that even at very early ages of colonization, the microbial ecosystem develops this circadian rhythmicity,” said senior author and microbiome expert Dirk Haller, PhD, a professor at the Technical University of Munich. “We have shown these rhythms before in adults, but we were not sure when these mechanisms first appear.”

While diet had only a marginal impact on infant microbiome development, the researchers showed that age plays a more important role.

“Diet matters, but less than aging of the gut,” said Haller. “When we compared breastfed and formula-fed infants, the differences in microbiome colonization were marginal. Our intestinal system is probably a little bit more flexible in adapting to what the environment has to offer.”

The researchers used a randomized controlled trial to compare microbiome development in infants that were exclusively breastfed with infants who received different types of formula—un-supplemented formula; formula containing breast-milk-derived bacteria (Bifidobacteria); formula containing breast-milk-mimicking sugars (galacto-oligosaccharides, GOSs); or formula containing both Bifidobacteria and GOSs. Altogether, the trial included 210 infants.

To longitudinally track the infants’ microbiomes, the team sampled the infants’ stools when they were 0.5 months, one month, three months, seven months, and 12 months of age as well as at 24 months for a subset of the infants.

The researchers found that diet had little impact on infant growth or the differences in the infants’ microbiomes. When they compared the different types of formula, they found that GOS-supplemented infant formula was more effective at promoting sustained levels of Bifidobacteria compared to formula containing Bifidobacteria.

However, there was a significant difference in the gut metabolite profile between exclusively breastfed and formula-fed infants. “The metabolite environment in the gut is dramatically different between a baby that is exclusively breastfed and babies that receive infant formula, which could have a fundamental impact on metabolic priming and many downstream effects,” said Haller. “We can conclude that breast milk does something completely different in the metabolism in the infant’s intestine.”

The researchers also observed rhythmic 24-hour fluctuations in the abundance of different microbiome species. When they took infant microbes and grew them in continuous culture in the lab, the bacteria settled into the same circadian rhythm—even in the absence of external light or host cues.

Though circadian rhythms have been previously observed in adult microbiomes, this is the first evidence that bacteria maintain these rhythms independently.

“When we take them out, they maintain these daytime-related diurnal oscillations,” Haller explained. “This is fairly surprising because it suggests that the bacteria have some intrinsic mechanism that provides some sort of adaptation to a day and night cycle, which could potentially give them an advantage in colonizing the human intestine.”

Looking toward the future, the researchers want to examine whether individual bacterial species maintain rhythms when grown in isolation rather than in complex communities and to search for the genes that control these rhythms.

“For us, the next question is can we identify mechanisms in bacteria that control their circadian behavior,” concluded Haller.

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