Alterations in enteric microbiota are associated with several highly prevalent immune-mediated and metabolic diseases1,2,3, and experiments involving faecal transplants have indicated that such alterations have a causal role in at least some such conditions4,5,6. The postnatal period is particularly critical for the development of microbiota composition, host–microbe interactions and immune homeostasis7,8,9. 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 REG3γ 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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We thank D. Gütle, T. Albers, M. Nietschke, A. Smoczek, V. Tremaroli and M. Krämer for technical support and M. Rühlemann for discussions. The work was supported by the priority programs SPP1656 (Ho-2236/9-1 and BL953/5-1) and SPP1580 (Ho 2236/11-1, He 1964/18-2), SFB944 (P4 to M.H.) and SFB1182 (C2 to F.S. and P.R.) and the single grant Ho 2236/14-1 from the German Research Foundation (DFG), as well as the Lower Saxony-Israel Fond and the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony, Germany, to M.F. and M.W.H. M.F. and K.v.V. were supported by the German Federal Ministry of Education and Research (BMBF) within the consortium InfectControl 2020 (Project NeoBiom, grant ID 03ZZ0829C). M.F. was supported by the Freie Universität Berlin within the Excellence Initiative of the DFG and P.R. by the ExC306 Inflammation at Interfaces. B.C. is supported by a Career Development Award from the Crohn’s and Colitis Foundation and an Innovator Award from the Kenneth Rainin Foundation. F.B. is Torsten Söderberg Professor in Medicine and recipient of ERC consolidator Grant 2013 (European Research Council, Consolidator grant 615362-METABASE).
Nature thanks J. Kagan and the other anonymous reviewer(s) for their contribution to the peer review of this work.