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

• Published in: Nature (London) Vol. 560; no. 7719; pp. 489 - 493
• Main Authors: Fulde, Marcus, Sommer, Felix, Chassaing, Benoit, van Vorst, Kira, Dupont, Aline, Hensel, Michael, Basic, Marijana, Klopfleisch, Robert, Rosenstiel, Philip, Bleich, André, Bäckhed, Fredrik, Gewirtz, Andrew T., Hornef, Mathias W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2018; Nature Publishing Group
• Subjects: 631/250/262/2106/2108; 631/326/2565/2134; 692/308/3187; acquisition; Age; Aging - genetics; Aging - immunology; Analysis; Animal experimentation; Animals; Animals, Newborn - genetics; Animals, Newborn - immunology; Bacteria; bacterial flagellin; Cell receptors; Clinical Medicine; colitis; Colonization; Composition; Crosses, Genetic; dendritic cells; Disease; Environment; Environmental factors; Epithelium; Experiments; Female; Flagellin; Flagellin - immunology; Flagellin - metabolism; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - immunology; Gene expression; Germfree; Homeostasis; Host Microbial Interactions; Housing, Animal; Humanities and Social Sciences; Immune system; infection; Infections; inflammation; Inflammatory bowel disease; Influence; intestinal microbiota; Intestinal microflora; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; Klinisk medicin; Letter; Male; Metabolic syndrome; Mice; Mice, Inbred C57BL; Microbiota; Microbiota (Symbiotic organisms); Molecular modelling; multidisciplinary; Neonatal screening; Neonates; Newborn babies; Newborn infants; Pregnancy; Priming; Proteins; Rodents; Salmonella; Science; Science & Technology - Other Topics; Science (multidisciplinary); shapes; TLR5 protein; tlr5-deficient mice; Toll-Like Receptor 5 - genetics; Toll-Like Receptor 5 - immunology; Toll-like receptors; Transplants; United States > US
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0395-5

Alterations in enteric microbiota are associated with several highly prevalent immune-mediated and metabolic diseases
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, and experiments involving faecal transplants have indicated that such alterations have a causal role in at least some such conditions
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. The postnatal period is particularly critical for the development of microbiota composition, host–microbe interactions and immune homeostasis
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. 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.
Age-dependent epithelial expression of the innate immune receptor TLR5 in the gut of newborn mice selects against the presence of flagellated bacteria and influences microbiota composition throughout life.