Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition

Marcus Fulde, Felix Sommer, Benoit Chassaing, Kira Vorst, Aline Dupont, Michael Hensel, Marijana Basic, Robert Klopfleisch, Philip Rosenstiel, André Bleich, Fredrik Bäckhed, Andrew T. Gewirtz and Mathias W. Hornef ()
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Marcus Fulde: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School
Felix Sommer: Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital
Benoit Chassaing: Neuroscience Institute, Georgia State University
Kira Vorst: Institute of Microbiology and Epizootics, Department of Veterinary Medicine at the Freie Universität Berlin
Aline Dupont: Institute for Medical Microbiology, RWTH University Hospital Aachen
Michael Hensel: University of Osnabrück
Marijana Basic: Institute for Laboratory Animal Science, Hannover Medical School
Robert Klopfleisch: Institute of Veterinary Pathology, Department of Veterinary Medicine at the Freie Universität Berlin
Philip Rosenstiel: Institute of Clinical Molecular Biology (IKMB), Kiel University
André Bleich: Institute for Laboratory Animal Science, Hannover Medical School
Fredrik Bäckhed: Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital
Andrew T. Gewirtz: Institute for Biomedical Sciences, Georgia State University
Mathias W. Hornef: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School

Nature, 2018, vol. 560, issue 7719, 489-493

Abstract: Abstract Alterations in enteric microbiota are associated with several highly prevalent immune-mediated and metabolic diseases1–3, and experiments involving faecal transplants have indicated that such alterations have a causal role in at least some such conditions4–6. The postnatal period is particularly critical for the development of microbiota composition, host–microbe interactions and immune homeostasis7–9. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0395-5

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