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Infants’ Microbiomes Have a Circadian Rhythm

    A clock to represent a GOS-supplemented formula that helps infants produce metabolites similar to breastfed infants, which show a 24-hour periodicity.

    Written by: Alla Katsnelson, Ph.D | Issue # 121 | 2024

    • The study aimed to explore what types of supplements make formula most similar to breast milk.
    • The metabolites produced by the bacteria differ in breastfed versus formula-fed infants, and infants fed formula supplemented with a type of milk sugar called galacto-oligosaccharides have metabolites most similar to those in breastfed infants.
    • Bacteria in infant microbiomes fluctuate in abundance over a 24-hour cycle.
    • The microbes retain a circadian rhythm even when grown outside of the body.

    Bacteria in the guts of infants as young as two weeks old fluctuate in abundance over a 24-hour period, according to a new study [1]. The gut microbiome in adults has a similar circadian rhythm, and growing evidence links its dysregulation to disease [2]. But researchers did not previously know at what point during development it emerges. 

    The study also found that the composition of metabolites in the gut – molecules produced by the gut microbiome — differed strongly between breastfed and formula-fed babies. The functional effects of this difference are not known, but “[w]e can conclude that breast milk does something completely different in the metabolism in the infants’ intestines,” says Dirk Haller, a microbiologist at the Technical University of Munich, in a press release. 

    The study is part of a longstanding effort among researchers to improve how well infant formula can approximate human milk. Special sugars in human milk are known to feed bifidobacteria. The researchers set out to test how well different supplements in formula boosted levels of bifidobacteria in infants’ guts. In a randomized controlled trial consisting of 210 infants, they gave infants formula alone, formula containing bifidobacteria, formula containing milk sugars called galacto-oligosaccarides (GOS), and formula containing both bifidobacteria and GOS. The researchers compared the effects of these different versions of formula to the effects of breast feeding on the gut microbiomes by collecting stool samples from infants at age 2 weeks, 3 months, 7 months, 12 months, and 24 months. They also compared stool samples taken in the daytime to those taken at night.

    The diversity of bacteria increased over time in all the groups, and the composition of the microbial communities varied widely across individuals. Diet only minimally affected   microbiome development compared to age, as the microbiome is highly dynamic during the first two years. Overall, the researchers found that the formula supplemented with GOS did a better job of boosting numbers of bifidobacteria—microbial species  thought to be health-promoting—compared to other formulas studied [3]. 

    The researchers analyzed the composition of metabolites in the different groups at three months – the timepoint at which infants would consume the highest amount of milk or formula but not yet solid foods. Metabolite profiles in the formula-fed groups were significantly different from the breastfed group, they found. “None of the three types of supplementation investigated in this study were able to fully recreate the breastmilk-related microbial environment,” the authors write in the paper. 

    In all groups, however, both metabolite and microbial composition fluctuated rhythmically over a 24-hour cycle. This phenomenon was present in all groups examined but grew stronger over time. The number of rhythmic bacteria increased over time, however, as infants began to eat foods beyond breastmilk or formula. The researchers also grew bacteria from the 3-month stool samples and found that they had a circadian rhythm even in a dish outside the microbiome. 

    Previous work has shown that the circadian rhythm of the gut microbiome in adults both affects and is affected by the circadian rhythm of the human host [4]. The fact that this periodicity is seen in infants “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,” said Haller in the press release.  

    Many questions remain about how exactly the bacteria regulate their circadian behavior, the authors write. They plan to search for the genes regulating these rhythms and to examine whether individual species are able to do so apart from the community as a whole.  

    References

    1. Heppner N, Reitmeier S, Heddes M, Merino MV, Schwartz L, Dietrich A, List M, Gigl M, Meng C, van der Veen DR, Schirmer M, Kleigrewe K, Omer H, Kiessling S, Haller D. Diurnal rhythmicity of infant fecal microbiota and metabolites: A randomized controlled interventional trial with infant formula. Cell Host Microbe. 2024 Apr 10;32(4):573-587.e5.
    2. Reitmeier S, Kiessling S, Clavel T, List M, Almeida EL, Ghosh TS, Neuhaus K, Grallert H, Linseisen J, Skurk T, Brandl B, Breuninger TA, Troll M, Rathmann W, Linkohr B, Hauner H, Laudes M, Franke A, Le Roy CI, Bell JT, Spector T, Baumbach J, O’Toole PW, Peters A, Haller D. Arrhythmic Gut Microbiome Signatures Predict Risk of Type 2 Diabetes. Cell Host Microbe. 2020 Aug 12;28(2):258-272.e6.
    3. Liu J, Tan Y, Cheng H, Zhang D, Feng W, Peng C. Functions of Gut Microbiota Metabolites, Current Status and Future Perspectives. Aging Dis. 2022 Jul 11;13(4):1106-1126.
    4. Heddes M, Altaha B, Niu Y, Reitmeier S, Kleigrewe K, Haller D, Kiessling S. The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis. Nat Commun. 2022 Oct 14;13(1):6068.