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First Encounters
Leading Edge
Select First Encounters The role of the microbiome across a range of physiological process is undebatable, but how this complex community is assembled and regulated remains only partially understood. Recent studies focused on a single sensor show that the neonatal period may represent a critical window and that immune interactions at this time could durably influence the members of the microbiome. As the collection of pictures accumulated within the first few years will tell you, babies change almost every day. However, the microbial changes occurring on the inside are as tantalizing, if not more, as the ones occurring on the outside. In a recent study, Hornef and collegues demonstrate that TLR5, a sensor of microbial flagellin, influences the composition of the gut microbiome specifically during that key period (Fulde et al., 2018). Surveys of the gut microbiome of infants and adults across the world have shown that the microbiome of children progressively evolves over a few years, particularly as diets shift from milk to more diverse solid foods (Yatsunenko et al., 2012). This idea is consistent with the strong role of nutrient sources in shaping the microbiome. Indeed, studies that have looked at the influence of host genetics on the microbiome have reported only modest effects, with heritability being limited to a few species in twin studies (Goodrich et al., 2014) or being largely undetectable in the general population (Rothschild et al., 2018). Examining this question from the lens of the host genes yielded similar conclusions, with the majority of genes that influence the composition of the gut microbiome related to diet. For example, the abundance of Bifidobacterium is strongly linked to a polymorphism in LCT, the gene encoding lactase and thus controlling lactose tolerance or intolerance (Blekhman et al., 2015). Nevertheless, studies in the field have also uncovered a few immune sensors that associate with increased or decreased levels of given species, sug-
Image from istockphoto/Tassii
gesting that in some cases innate sensing by the host may regulate colonization (Kurilshikov, Wijmenga, Fu, & Zhernakova, 2017). The flagellin sensor TLR5 has been associated with microbial alterations in mice and represents an interesting system to evaluate the regulation of the microbiome by the host. The authors first examined the expression of Tlr5 in the small intestine across the lifespan of the mouse and discovered that expression of the receptor by intestinal epithelial cells (IEC) is almost abolished after weaning. This suggests that TLR5 sensing can only occur in neonates; and indeed, using a Salmonella model, the authors can show that non-flagellated bacteria have a competitive advantage in young animals, but not in adults. To show that this effect more broadly regulates the composition of the microbiome, the authors had to devise models that allowed them to separate the effects of host genotype, age, and microbe transfer from mothers and among littermates, highlighting the complexity of examining these effects even in experimental systems (not to mention in the real world for human studies). Using a combination of wild-type and Tlr5-deficient dams that were co-housed during gestation but separated right before the birth of the pups, they show that TLR5 can control the composition of the microbiome in neonates, an effect that is overshadowed by microbiota transfer in the context of heterozygous matings. Using germ-free mice as recipients, they also demonstrate that this TLR5-dependent selection is age dependent but that once these differences are established, they will persist during adulthood. These results suggest that the neonatal period may represent a critical window for the establishment of the microbiome, although it remains to be seen whether these findings would also hold in a more variable environment, where diet and conditions keep shifting far into adulthood. Regardless, the fact that the host directly regulates Tlr5 levels in the intestine during development suggests that this strategy may play an adaptive role in the delicate balance between the regulation of local pathogens and commensals and the avoidance of unnecessary inflammation. Of note, while overall Tlr5 levels decrease in adults, Paneth cells appear to maintain the expression of this receptor, as recently shown in a survey of TLR expression in the gut (Price et al., 2018). Paneth cells are located at the bottom of the crypts present in the small intestine and function as specialized antimicrobial peptide producers. This suggests that they may represent another solution in this compromise between detection and avoidance of inflammation, since flagellin signaling by these cells may only occur when bacteria have accessed crypts. Interestingly, Cell 175, October 18, 2018 ª 2018 Elsevier Inc. 601
this study also reveals that the downregulation of Tlr5 occurs in germ-free animals, implying that this process is host-intrinsic. Altogether, these mouse studies provide important molecular insights into the complex interplay between host sensors and microbes and suggest that these interactions may be particularly important in the neonatal period, as the microbial community is being assembled and likely to be less stable. How these insights translate to human remain to be shown, and much remains to be learned about the specifics of the neonatal immune system, but it appears clear that the host has evolved ways to tune its responses to these first encounters, whose influence might extend well beyond the first few years. REFERENCES Blekhman, R., Goodrich, J.K., Huang, K., Sun, Q., Bukowski, R., Bell, J.T., Spector, T.D., Keinan, A., Ley, R.E., Gevers, D., and Clark, A.G. (2015). Host genetic variation impacts microbiome composition across human body sites. Genome Biol. 16, 191. Fulde, M., Sommer, F., Chassaing, B., van Vorst, K., Dupont, A., Hensel, M., Basic, M., Klopfleisch, R., Rosenstiel, P., Bleich, A., et al. (2018). Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition. Nature 560, 489–493. Goodrich, J.K., Waters, J.L., Poole, A.C., Sutter, J.L., Koren, O., Blekhman, R., Beaumont, M., Van Treuren, W., Knight, R., Bell, J.T., et al. (2014). Human genetics shape the gut microbiome. Cell 159, 789–799. Kurilshikov, A., Wijmenga, C., Fu, J., and Zhernakova, A. (2017). Host Genetics and Gut Microbiome: Challenges and Perspectives. Trends Immunol. 38, 633–647. Price, A.E., Shamardani, K., Lugo, K.A., Deguine, J., Roberts, A.W., Lee, B.L., and Barton, G.M. (2018). A Map of Toll-like Receptor Expression in the Intestinal Epithelium Reveals Distinct Spatial, Cell Type-Specific, and Temporal Patterns. Immunity 49, 560–575.e6. Rothschild, D., Weissbrod, O., Barkan, E., Kurilshikov, A., Korem, T., Zeevi, D., Costea, P.I., Godneva, A., Kalka, I.N., Bar, N., et al. (2018). Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215. 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). Human gut microbiome viewed across age and geography. Nature 486, 222–227.
Jacques Deguine
Cell 175, October 18, 2018 603
Select First Encounters The role of the microbiome across a range of physiological process is undebatable, but how this complex community is assembled and regulated remains only partially understood. Recent studies focused on a single sensor show that the neonatal period may represent a critical window and that immune interactions at this time could durably influence the members of the microbiome. As the collection of pictures accumulated within the first few years will tell you, babies change almost every day. However, the microbial changes occurring on the inside are as tantalizing, if not more, as the ones occurring on the outside. In a recent study, Hornef and collegues demonstrate that TLR5, a sensor of microbial flagellin, influences the composition of the gut microbiome specifically during that key period (Fulde et al., 2018). Surveys of the gut microbiome of infants and adults across the world have shown that the microbiome of children progressively evolves over a few years, particularly as diets shift from milk to more diverse solid foods (Yatsunenko et al., 2012). This idea is consistent with the strong role of nutrient sources in shaping the microbiome. Indeed, studies that have looked at the influence of host genetics on the microbiome have reported only modest effects, with heritability being limited to a few species in twin studies (Goodrich et al., 2014) or being largely undetectable in the general population (Rothschild et al., 2018). Examining this question from the lens of the host genes yielded similar conclusions, with the majority of genes that influence the composition of the gut microbiome related to diet. For example, the abundance of Bifidobacterium is strongly linked to a polymorphism in LCT, the gene encoding lactase and thus controlling lactose tolerance or intolerance (Blekhman et al., 2015). Nevertheless, studies in the field have also uncovered a few immune sensors that associate with increased or decreased levels of given species, sug-
Image from istockphoto/Tassii
gesting that in some cases innate sensing by the host may regulate colonization (Kurilshikov, Wijmenga, Fu, & Zhernakova, 2017). The flagellin sensor TLR5 has been associated with microbial alterations in mice and represents an interesting system to evaluate the regulation of the microbiome by the host. The authors first examined the expression of Tlr5 in the small intestine across the lifespan of the mouse and discovered that expression of the receptor by intestinal epithelial cells (IEC) is almost abolished after weaning. This suggests that TLR5 sensing can only occur in neonates; and indeed, using a Salmonella model, the authors can show that non-flagellated bacteria have a competitive advantage in young animals, but not in adults. To show that this effect more broadly regulates the composition of the microbiome, the authors had to devise models that allowed them to separate the effects of host genotype, age, and microbe transfer from mothers and among littermates, highlighting the complexity of examining these effects even in experimental systems (not to mention in the real world for human studies). Using a combination of wild-type and Tlr5-deficient dams that were co-housed during gestation but separated right before the birth of the pups, they show that TLR5 can control the composition of the microbiome in neonates, an effect that is overshadowed by microbiota transfer in the context of heterozygous matings. Using germ-free mice as recipients, they also demonstrate that this TLR5-dependent selection is age dependent but that once these differences are established, they will persist during adulthood. These results suggest that the neonatal period may represent a critical window for the establishment of the microbiome, although it remains to be seen whether these findings would also hold in a more variable environment, where diet and conditions keep shifting far into adulthood. Regardless, the fact that the host directly regulates Tlr5 levels in the intestine during development suggests that this strategy may play an adaptive role in the delicate balance between the regulation of local pathogens and commensals and the avoidance of unnecessary inflammation. Of note, while overall Tlr5 levels decrease in adults, Paneth cells appear to maintain the expression of this receptor, as recently shown in a survey of TLR expression in the gut (Price et al., 2018). Paneth cells are located at the bottom of the crypts present in the small intestine and function as specialized antimicrobial peptide producers. This suggests that they may represent another solution in this compromise between detection and avoidance of inflammation, since flagellin signaling by these cells may only occur when bacteria have accessed crypts. Interestingly, Cell 175, October 18, 2018 ª 2018 Elsevier Inc. 601
this study also reveals that the downregulation of Tlr5 occurs in germ-free animals, implying that this process is host-intrinsic. Altogether, these mouse studies provide important molecular insights into the complex interplay between host sensors and microbes and suggest that these interactions may be particularly important in the neonatal period, as the microbial community is being assembled and likely to be less stable. How these insights translate to human remain to be shown, and much remains to be learned about the specifics of the neonatal immune system, but it appears clear that the host has evolved ways to tune its responses to these first encounters, whose influence might extend well beyond the first few years. REFERENCES Blekhman, R., Goodrich, J.K., Huang, K., Sun, Q., Bukowski, R., Bell, J.T., Spector, T.D., Keinan, A., Ley, R.E., Gevers, D., and Clark, A.G. (2015). Host genetic variation impacts microbiome composition across human body sites. Genome Biol. 16, 191. Fulde, M., Sommer, F., Chassaing, B., van Vorst, K., Dupont, A., Hensel, M., Basic, M., Klopfleisch, R., Rosenstiel, P., Bleich, A., et al. (2018). Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition. Nature 560, 489–493. Goodrich, J.K., Waters, J.L., Poole, A.C., Sutter, J.L., Koren, O., Blekhman, R., Beaumont, M., Van Treuren, W., Knight, R., Bell, J.T., et al. (2014). Human genetics shape the gut microbiome. Cell 159, 789–799. Kurilshikov, A., Wijmenga, C., Fu, J., and Zhernakova, A. (2017). Host Genetics and Gut Microbiome: Challenges and Perspectives. Trends Immunol. 38, 633–647. Price, A.E., Shamardani, K., Lugo, K.A., Deguine, J., Roberts, A.W., Lee, B.L., and Barton, G.M. (2018). A Map of Toll-like Receptor Expression in the Intestinal Epithelium Reveals Distinct Spatial, Cell Type-Specific, and Temporal Patterns. Immunity 49, 560–575.e6. Rothschild, D., Weissbrod, O., Barkan, E., Kurilshikov, A., Korem, T., Zeevi, D., Costea, P.I., Godneva, A., Kalka, I.N., Bar, N., et al. (2018). Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215. 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). Human gut microbiome viewed across age and geography. Nature 486, 222–227.
Jacques Deguine
Cell 175, October 18, 2018 603