Journal
NATURE
Volume 560, Issue 7719, Pages 489-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0395-5
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Funding
- German Research Foundation (DFG) [Ho 2236/14-1]
- Lower Saxony-Israel Fond
- Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony, Germany
- German Federal Ministry of Education and Research (BMBF) within the consortium InfectControl 2020 [03ZZ0829C]
- Freie Universitat Berlin within the Excellence Initiative of the DFG
- Crohn's and Colitis Foundation
- Kenneth Rainin Foundation
- ERC consolidator Grant 2013 (European Research Council) [615362-METABASE]
- [SPP1656]
- [Ho-2236/9-1]
- [BL953/5-1]
- [SPP1580]
- [Ho 2236/11-1]
- [He 1964/18-2]
- [SFB944]
- [SFB1182]
- [ExC306]
- Crohn"
- s & Colitis Foundation of America [370295] Funding Source: researchfish
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Alterations in enteric microbiota are associated with several highly prevalent immune-mediated and metabolic diseases(1-3), and experiments involving faecal transplants have indicated that such alterations have a causal role in at least some such conditions(4-6). The postnatal period is particularly critical for the development of microbiota composition, host-microbe interactions and immune homeostasis(7-9). However, the underlying molecular mechanisms of this neonatal priming period have not been defined. Here we report the identification of a host-mediated regulatory circuit of bacterial colonization that acts solely during the early neonatal period but influences life-long microbiota composition. We demonstrate age-dependent expression of the flagellin receptor Toll-like receptor 5 (TLR5) in the gut epithelium of neonate mice. Using competitive colonization experiments, we demonstrate that epithelial TLR5-mediated REG3 gamma production is critical for the counter-selection of colonizing flagellated bacteria. Comparative microbiota transfer experiments in neonate and adult wild-type and Tlr5-deficient germ-free mice reveal that neonatal TLR5 expression strongly influences the composition of the microbiota throughout life. Thus, the beneficial microbiota in the adult host is shaped during early infancy. This might explain why environmental factors that disturb the establishment of the microbiota during early life can affect immune homeostasis and health in adulthood.
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