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Rapid fucosylation of intestinal epithelium sustains host–commensal symbiosis in sickness

2014; Nature Portfolio; Volume: 514; Issue: 7524 Linguagem: Inglês

10.1038/nature13823

1476-4687

Joseph M. Pickard, Corinne F. Maurice, Melissa A. Kinnebrew, Michael C. Abt, Dominik Schenten, Tatyana V. Golovkina, Said R. Bogatyrev, Rustem F. Ismagilov, Eric G. Pamer, Peter J. Turnbaugh, Alexander V. Chervonsky,

IL-33, ST2, and ILC Pathways

Systemic exposure to Toll-like receptor (TLR) ligands during sickness is shown to induce fucosylation of the small intestine in mice; some of the fucose is shed into the intestinal lumen, where it provides nourishment for the microbiota. A healthy gut microbiota is important for the host's well being, so it would make sense for host resources to be expended to protect 'good' microbes during a systemic response to infection. L-fucosylation could be such a resource: L-fucose attached to glycoproteins and glycolipids is accessible for microbial, but not for host energy harvest. Joseph Pickard et al. show that systemic exposure to Toll-like receptor (TLR) ligands induces fucosylation of the small intestine epithelium via a dendritic cell and interleukin-22 (IL-22) dependent mechanism. Some of the fucose is shed into the intestinal lumen where it provides nourishment for the microbiota, and contributes to the production of short-chain fatty acids, which are beneficial for the host. Systemic infection induces conserved physiological responses that include both resistance and ‘tolerance of infection’ mechanisms1. Temporary anorexia associated with an infection is often beneficial2,3, reallocating energy from food foraging towards resistance to infection4 or depriving pathogens of nutrients5. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections)6. We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host’s resources to maintain host–microbial interactions during pathogen-induced stress.