Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition.
Fulde M, Sommer F, Chassaing B, van Vorst K, Dupont A, Hensel M, Basic M, Klopfleisch R, Rosenstiel P, Bleich A, Bäckhed F, Gewirtz AT, Hornef MW
Nature. Aug 2018. doi: 10.1038/s41586-018-0395-5
COMMENT: This publication shows how TLR5, a member of the Toll-like receptors that plays a fundamental role in pathogen recognition and activation of innate immune responses, is a key factor in the shaping of the peculiarities of the individual microbiota throughout all life. TLR5 receptors recognize distinct pathogen-associated molecular patterns that are expressed on motile infectious bacteria. They recognize bacterial flagellin, the principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-kappaB, which in turn activates a host of inflammatory-related target genes. Mutations in this gene have been associated with both resistance and susceptibility to systemic lupus erythematosus, inflammatory bowel diseases and other autoimmune diseases.
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.
As it is shown in the image the structure of full-length human TLR5 determined by electron microscopy single-particle image reconstruction at 26Å resolution shows that TLR5 forms an asymmetric homodimer via ectodomain interactions. The structure shows that like TLR9, TLR5 dimerizes in the absence of ligand. The asymmetry of the dimer suggests that TLR5 may recognize two flagellin molecules cooperatively to establish an optimal flagellin response threshold.
This work demonstrates that epithelial Tlr5 expression in the postnatal period influences microbiota composition in adulthood and might affect susceptibility to metabolic dysfunction and inflammation in adult mice. Based on these new findings probably it will be possible to develop new manners of favouring the development of a healthy microbiota and of preventing some autoinmune diseases.