Cell Host & Microbe
Previews the circadian clock respond to changes in diet. Consistent with previous studies, germ-free mice are more resistant to diet-induced obesity than mice with gut microbiota (Ba¨ckhed et al., 2007; Rabot et al., 2010). Also consistent with previous work, Leone et al. (2015) found that a high-fat diet caused altered levels of host circadian transcripts (Eckel-Mahan et al., 2013). Leone et al. (2015) took this work one step further and found that a high-fat diet caused changes in bacterial composition and circadian oscillations, as well as bacterially produced metabolites. Taken together with their other data and the known effects of circadian regulation on metabolism, Leone et al. (2015) propose that bi-directional communication between the gut microbiota and the host clock might contribute to diet-induced obesity (Figure 1). Whether diet-induced obesity is indeed facilitated by the effects of bacterial metabolites or another ‘‘message in a biota’’ affecting the host molecular clock remains an exciting avenue for future experiments. The work of Leone et al. (2015), in combination with other recent studies
(Mukherji et al., 2013; Thaiss et al., 2014; Voigt et al., 2014), has identified the circadian clock as a potentially crucial mediator of the influence our microbiota exerts on our health. This will enhance our understanding and treatment of the health problems affecting individuals with disrupted circadian rhythm, such as shift workers and frequent fliers. Furthermore, ongoing research can utilize the well-studied molecular clock components and their targets as starting points for uncovering specific molecular links between the microbiota and physiological processes, thereby aiding the development of effective therapeutics for metabolic disorders.
Eckel-Mahan, K.L., Patel, V.R., de Mateo, S., Orozco-Solis, R., Ceglia, N.J., Sahar, S., Dilag-Penilla, S.A., Dyar, K.A., Baldi, P., and Sassone-Corsi, P. (2013). Cell 155, 1464–1478.
ACKNOWLEDGMENTS
Rabot, S., Membrez, M., Bruneau, A., Ge´rard, P., Harach, T., Moser, M., Raymond, F., Mansourian, R., and Chou, C.J. (2010). FASEB J. 24, 4948– 4959.
We are grateful to everyone in the Shirasu-Hiza lab for their support. This work was supported by NIH R01 AG045842, NIH R01 GM105775, and the Irma T. Hirschl Career award to M.M.S.-H.
Gareau, M.G. (2014). Adv. Exp. Med. Biol. 817, 357–371. Hooper, L.V., Littman, D.R., and Macpherson, A.J. (2012). Science 336, 1268–1273. Leone, V., Gibbons, S.M., Martinez, K., Hutchison, A.L., Huang, E.Y., Cham, C.M., Pierre, J.F., Heneghan, A.F., Nadimpalli, A., Hubert, N., et al. (2015). Cell Host Microbe 17, this issue, 681–689. Mukherji, A., Kobiita, A., Ye, T., and Chambon, P. (2013). Cell 153, 812–827. Partch, C.L., Green, C.B., and Takahashi, J.S. (2014). Trends Cell Biol. 24, 90–99.
REFERENCES
Thaiss, C.A., Zeevi, D., Levy, M., Zilberman-Schapira, G., Suez, J., Tengeler, A.C., Abramson, L., Katz, M.N., Korem, T., Zmora, N., et al. (2014). Cell 159, 514–529.
Ba¨ckhed, F., Manchester, J.K., Semenkovich, C.F., and Gordon, J.I. (2007). Proc. Natl. Acad. Sci. USA 104, 979–984.
Voigt, R.M., Forsyth, C.B., Green, S.J., Mutlu, E., Engen, P., Vitaterna, M.H., Turek, F.W., and Keshavarzian, A. (2014). PLoS ONE 9, e97500.
Birth of the Infant Gut Microbiome: Moms Deliver Twice! Steven A. Frese1 and David A. Mills1,* 1Department of Food Science and Technology, University of California Davis and the Foods For Health Institute, University of California Davis, Davis, CA 95616, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2015.04.014
The infant gut is rapidly colonized by microbes shortly after birth. In this issue of Cell Host & Microbe, Ba¨ckhed et al. (2015) shed new light on the assembly of the infant gut microbiome early in life, and how diet and delivery mode shape this community in a western human population. After the relative sterility of the uterus, exposure at birth and to the environment results in a rapid colonization of the gut by microbes. Several studies have described this early community assembly (Subramanian et al., 2014; Yatsunenko et al., 2012), and now Ba¨ckhed et al. (2015) analyze the microbiome of a large
cohort of Swedish infants to show how specific species in this community colonize the host. By sampling the gut microbiome of these infants and their mothers through the first year of life, the authors identify a number of features contributing to this early assembly. Using shotgun metagenomic sequencing, the
authors constructed MetaOTUs (Operational Taxonomic Units [OTUs]), representing functional and taxonomic information from whole genomes, assembled into over 5,500 different bacterial or archaeal genomes. Using this wealth of information, the authors made several key discoveries.
Cell Host & Microbe 17, May 13, 2015 ª2015 Elsevier Inc. 543
Cell Host & Microbe
Previews First, while delivery mode has been described as a prime difference in shaping the gut microbiome shortly after birth (Dominguez-Bello et al., 2010), Ba¨ckhed et al. (2015) identified strainspecific links between the mother’s fecal microbiome and the infant’s microbiome early in life. This link is broken more frequently in children born by cesarean section, and it appears that vaginal delivery provides a source of key gut microbes to the infant gut, not from the vagina, but via a fecal-oral route, in agreement with strain-specific typing methods used in previous studies (Makino et al., 2013; Tannock et al., 1990). Surprisingly, this serves as a way to promote the inoculation of key gut microbes such as Bifidobacterium longum, which is linked with beneficial immune responses early in life (Huda et al., 2014). Ba¨ckhed et al. (2015) showed how vaginal delivery, by comparison to cesarean birth, reduced the stochasticity in the assembly of the neonate gut microbiota. While differences between cesarean and vaginally delivered infants decreased over the course of the first year of life, the gut microbiota of cesarean section-born infants was more heterogeneous as a population than vaginally delivered infants. After birth, infants fed mother’s milk had comparatively reduced alpha diversity (diversity within a sample), as a result of the arsenal of tools that human milk provides to modulate the infant gut microbiota including soluble immunoglobins, lactoferrin, lysozyme as well as an array of structurally complex milk glycans (Pacheco et al., 2015). Ba¨ckhed and coworkers revealed the influence of milk glycans by observing a unique enrichment of specific functional pathways needed to consume these glycans in breast-fed infants. Interestingly, formula-fed infants had more diverse gut microbial communities, but this was typified by higher pop-
ulations of Clostridium, Franulicatella, Citrobacter, Enterobacter, and Bilophila relative to breast-fed infants and, functionally, these infants hosted higher proportions of antibiotic resistance genes, especially from g-Proteobacteria. This suggests that there may be previously unconsidered benefits from breastfeeding; including the possibility to reduce exposure to populations of microbes that contribute to the abundance of antibiotic resistance. As the infants aged, these gut carbohydrate consumption pathways changed to reflect changes in dietary substrates. Over time, with increasing dietary complexity at 12 months of age, the metabolic networks in the gut of these infants similarly increased in complexity as the number of taxa increased. However, in a surprising development, it was the cessation of breastfeeding, rather than introduction of novel foods, that coincided with the transition to a more ‘‘adult-like’’ microbiome. Despite the increasing understanding of how host-microbe interactions in the gut shape so many aspects of human development, it is still surprising to observe a concerted process that facilitates the inter-generational transfer of microbes from mother to infant. Further, the active suppression of community diversity by the constellation of microbially active factors in breast milk represents an interesting evolutionary model on a guided process of gut colonization. Given how western lifestyles such as formula feeding, a highly processed diet, antibiotic use, sanitized water, and waste disposal have likely changed the composition of human gut microbiomes, it is especially timely to consider how that early gut microbiome is passed from one generation to the next. Indeed, Ba¨ckhed et al. (2015) ponder, how this early relationship contributes to the ‘‘priming’’ of
544 Cell Host & Microbe 17, May 13, 2015 ª2015 Elsevier Inc.
the gut microbiome, and how trajectories established in early life may shape later gut microbial populations—questions especially pertinent given the increasing prevalence of ‘‘western’’ diseases such as atopy and allergy. How a healthy microbiome is established with potentially life-long consequences is just one more lesson we clearly need to learn from our Mothers. ACKNOWLEDGMENTS We acknowledge support from the National Institutes of Health Ruth L. Kirschstein NRSA Postdoctoral Fellowship (S.A.F.) and awards R01AT007079 and R01AT008759 (D.A.M). D.A.M. is a co-founder of Evolve Biosystems, a company focused on dietbased manipulation of the gut microbiota. REFERENCES Ba¨ckhed, F., Roswall, J., Peng, Y., Feng, Q., Jia, H., Kovatcheva-Datchary, P., Li, Y., Xia, Y., Xie, H., Zhong, H., et al. (2015). Cell Host Microbe 17, this issue, 690–703. Dominguez-Bello, M.G., Costello, E.K., Contreras, M., Magris, M., Hidalgo, G., Fierer, N., and Knight, R. (2010). Proc. Natl. Acad. Sci. USA 107, 11971– 11975. Huda, M.N., Lewis, Z., Kalanetra, K.M., Rashid, M., Ahmad, S.M., Raqib, R., Qadri, F., Underwood, M.A., Mills, D.A., and Stephensen, C.B. (2014). Pediatrics 134, e362–e372. Makino, H., Kushiro, A., Ishikawa, E., Kubota, H., Gawad, A., Sakai, T., Oishi, K., Martı´n, R., BenAmor, K., Knol, J., and Tanaka, R. (2013). PLoS ONE 8, e78331. Pacheco, A.R., Barile, D., Underwood, M.A., and Mills, D.A. (2015). Annu. Rev. Anim. Biosci. 3, 419–445. Subramanian, S., Huq, S., Yatsunenko, T., Haque, R., Mahfuz, M., Alam, M.A., Benezra, A., DeStefano, J., Meier, M.F., Muegge, B.D., et al. (2014). Nature 510, 417–421. Tannock, G.W., Fuller, R., Smith, S.L., and Hall, M.A. (1990). J. Clin. Microbiol. 28, 1225– 1228. Yatsunenko, T., Rey, F.E., Manary, M.J., Trehan, I., Dominguez-Bello, M.G., Contreras, M., Magris, M., Hidalgo, G., Baldassano, R.N., Anokhin, A.P., et al. (2012). Nature 486, 222–227.
Previews the circadian clock respond to changes in diet. Consistent with previous studies, germ-free mice are more resistant to diet-induced obesity than mice with gut microbiota (Ba¨ckhed et al., 2007; Rabot et al., 2010). Also consistent with previous work, Leone et al. (2015) found that a high-fat diet caused altered levels of host circadian transcripts (Eckel-Mahan et al., 2013). Leone et al. (2015) took this work one step further and found that a high-fat diet caused changes in bacterial composition and circadian oscillations, as well as bacterially produced metabolites. Taken together with their other data and the known effects of circadian regulation on metabolism, Leone et al. (2015) propose that bi-directional communication between the gut microbiota and the host clock might contribute to diet-induced obesity (Figure 1). Whether diet-induced obesity is indeed facilitated by the effects of bacterial metabolites or another ‘‘message in a biota’’ affecting the host molecular clock remains an exciting avenue for future experiments. The work of Leone et al. (2015), in combination with other recent studies
(Mukherji et al., 2013; Thaiss et al., 2014; Voigt et al., 2014), has identified the circadian clock as a potentially crucial mediator of the influence our microbiota exerts on our health. This will enhance our understanding and treatment of the health problems affecting individuals with disrupted circadian rhythm, such as shift workers and frequent fliers. Furthermore, ongoing research can utilize the well-studied molecular clock components and their targets as starting points for uncovering specific molecular links between the microbiota and physiological processes, thereby aiding the development of effective therapeutics for metabolic disorders.
Eckel-Mahan, K.L., Patel, V.R., de Mateo, S., Orozco-Solis, R., Ceglia, N.J., Sahar, S., Dilag-Penilla, S.A., Dyar, K.A., Baldi, P., and Sassone-Corsi, P. (2013). Cell 155, 1464–1478.
ACKNOWLEDGMENTS
Rabot, S., Membrez, M., Bruneau, A., Ge´rard, P., Harach, T., Moser, M., Raymond, F., Mansourian, R., and Chou, C.J. (2010). FASEB J. 24, 4948– 4959.
We are grateful to everyone in the Shirasu-Hiza lab for their support. This work was supported by NIH R01 AG045842, NIH R01 GM105775, and the Irma T. Hirschl Career award to M.M.S.-H.
Gareau, M.G. (2014). Adv. Exp. Med. Biol. 817, 357–371. Hooper, L.V., Littman, D.R., and Macpherson, A.J. (2012). Science 336, 1268–1273. Leone, V., Gibbons, S.M., Martinez, K., Hutchison, A.L., Huang, E.Y., Cham, C.M., Pierre, J.F., Heneghan, A.F., Nadimpalli, A., Hubert, N., et al. (2015). Cell Host Microbe 17, this issue, 681–689. Mukherji, A., Kobiita, A., Ye, T., and Chambon, P. (2013). Cell 153, 812–827. Partch, C.L., Green, C.B., and Takahashi, J.S. (2014). Trends Cell Biol. 24, 90–99.
REFERENCES
Thaiss, C.A., Zeevi, D., Levy, M., Zilberman-Schapira, G., Suez, J., Tengeler, A.C., Abramson, L., Katz, M.N., Korem, T., Zmora, N., et al. (2014). Cell 159, 514–529.
Ba¨ckhed, F., Manchester, J.K., Semenkovich, C.F., and Gordon, J.I. (2007). Proc. Natl. Acad. Sci. USA 104, 979–984.
Voigt, R.M., Forsyth, C.B., Green, S.J., Mutlu, E., Engen, P., Vitaterna, M.H., Turek, F.W., and Keshavarzian, A. (2014). PLoS ONE 9, e97500.
Birth of the Infant Gut Microbiome: Moms Deliver Twice! Steven A. Frese1 and David A. Mills1,* 1Department of Food Science and Technology, University of California Davis and the Foods For Health Institute, University of California Davis, Davis, CA 95616, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2015.04.014
The infant gut is rapidly colonized by microbes shortly after birth. In this issue of Cell Host & Microbe, Ba¨ckhed et al. (2015) shed new light on the assembly of the infant gut microbiome early in life, and how diet and delivery mode shape this community in a western human population. After the relative sterility of the uterus, exposure at birth and to the environment results in a rapid colonization of the gut by microbes. Several studies have described this early community assembly (Subramanian et al., 2014; Yatsunenko et al., 2012), and now Ba¨ckhed et al. (2015) analyze the microbiome of a large
cohort of Swedish infants to show how specific species in this community colonize the host. By sampling the gut microbiome of these infants and their mothers through the first year of life, the authors identify a number of features contributing to this early assembly. Using shotgun metagenomic sequencing, the
authors constructed MetaOTUs (Operational Taxonomic Units [OTUs]), representing functional and taxonomic information from whole genomes, assembled into over 5,500 different bacterial or archaeal genomes. Using this wealth of information, the authors made several key discoveries.
Cell Host & Microbe 17, May 13, 2015 ª2015 Elsevier Inc. 543
Cell Host & Microbe
Previews First, while delivery mode has been described as a prime difference in shaping the gut microbiome shortly after birth (Dominguez-Bello et al., 2010), Ba¨ckhed et al. (2015) identified strainspecific links between the mother’s fecal microbiome and the infant’s microbiome early in life. This link is broken more frequently in children born by cesarean section, and it appears that vaginal delivery provides a source of key gut microbes to the infant gut, not from the vagina, but via a fecal-oral route, in agreement with strain-specific typing methods used in previous studies (Makino et al., 2013; Tannock et al., 1990). Surprisingly, this serves as a way to promote the inoculation of key gut microbes such as Bifidobacterium longum, which is linked with beneficial immune responses early in life (Huda et al., 2014). Ba¨ckhed et al. (2015) showed how vaginal delivery, by comparison to cesarean birth, reduced the stochasticity in the assembly of the neonate gut microbiota. While differences between cesarean and vaginally delivered infants decreased over the course of the first year of life, the gut microbiota of cesarean section-born infants was more heterogeneous as a population than vaginally delivered infants. After birth, infants fed mother’s milk had comparatively reduced alpha diversity (diversity within a sample), as a result of the arsenal of tools that human milk provides to modulate the infant gut microbiota including soluble immunoglobins, lactoferrin, lysozyme as well as an array of structurally complex milk glycans (Pacheco et al., 2015). Ba¨ckhed and coworkers revealed the influence of milk glycans by observing a unique enrichment of specific functional pathways needed to consume these glycans in breast-fed infants. Interestingly, formula-fed infants had more diverse gut microbial communities, but this was typified by higher pop-
ulations of Clostridium, Franulicatella, Citrobacter, Enterobacter, and Bilophila relative to breast-fed infants and, functionally, these infants hosted higher proportions of antibiotic resistance genes, especially from g-Proteobacteria. This suggests that there may be previously unconsidered benefits from breastfeeding; including the possibility to reduce exposure to populations of microbes that contribute to the abundance of antibiotic resistance. As the infants aged, these gut carbohydrate consumption pathways changed to reflect changes in dietary substrates. Over time, with increasing dietary complexity at 12 months of age, the metabolic networks in the gut of these infants similarly increased in complexity as the number of taxa increased. However, in a surprising development, it was the cessation of breastfeeding, rather than introduction of novel foods, that coincided with the transition to a more ‘‘adult-like’’ microbiome. Despite the increasing understanding of how host-microbe interactions in the gut shape so many aspects of human development, it is still surprising to observe a concerted process that facilitates the inter-generational transfer of microbes from mother to infant. Further, the active suppression of community diversity by the constellation of microbially active factors in breast milk represents an interesting evolutionary model on a guided process of gut colonization. Given how western lifestyles such as formula feeding, a highly processed diet, antibiotic use, sanitized water, and waste disposal have likely changed the composition of human gut microbiomes, it is especially timely to consider how that early gut microbiome is passed from one generation to the next. Indeed, Ba¨ckhed et al. (2015) ponder, how this early relationship contributes to the ‘‘priming’’ of
544 Cell Host & Microbe 17, May 13, 2015 ª2015 Elsevier Inc.
the gut microbiome, and how trajectories established in early life may shape later gut microbial populations—questions especially pertinent given the increasing prevalence of ‘‘western’’ diseases such as atopy and allergy. How a healthy microbiome is established with potentially life-long consequences is just one more lesson we clearly need to learn from our Mothers. ACKNOWLEDGMENTS We acknowledge support from the National Institutes of Health Ruth L. Kirschstein NRSA Postdoctoral Fellowship (S.A.F.) and awards R01AT007079 and R01AT008759 (D.A.M). D.A.M. is a co-founder of Evolve Biosystems, a company focused on dietbased manipulation of the gut microbiota. REFERENCES Ba¨ckhed, F., Roswall, J., Peng, Y., Feng, Q., Jia, H., Kovatcheva-Datchary, P., Li, Y., Xia, Y., Xie, H., Zhong, H., et al. (2015). Cell Host Microbe 17, this issue, 690–703. Dominguez-Bello, M.G., Costello, E.K., Contreras, M., Magris, M., Hidalgo, G., Fierer, N., and Knight, R. (2010). Proc. Natl. Acad. Sci. USA 107, 11971– 11975. Huda, M.N., Lewis, Z., Kalanetra, K.M., Rashid, M., Ahmad, S.M., Raqib, R., Qadri, F., Underwood, M.A., Mills, D.A., and Stephensen, C.B. (2014). Pediatrics 134, e362–e372. Makino, H., Kushiro, A., Ishikawa, E., Kubota, H., Gawad, A., Sakai, T., Oishi, K., Martı´n, R., BenAmor, K., Knol, J., and Tanaka, R. (2013). PLoS ONE 8, e78331. Pacheco, A.R., Barile, D., Underwood, M.A., and Mills, D.A. (2015). Annu. Rev. Anim. Biosci. 3, 419–445. Subramanian, S., Huq, S., Yatsunenko, T., Haque, R., Mahfuz, M., Alam, M.A., Benezra, A., DeStefano, J., Meier, M.F., Muegge, B.D., et al. (2014). Nature 510, 417–421. Tannock, G.W., Fuller, R., Smith, S.L., and Hall, M.A. (1990). J. Clin. Microbiol. 28, 1225– 1228. Yatsunenko, T., Rey, F.E., Manary, M.J., Trehan, I., Dominguez-Bello, M.G., Contreras, M., Magris, M., Hidalgo, G., Baldassano, R.N., Anokhin, A.P., et al. (2012). Nature 486, 222–227.
