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Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness.

Pickard JM, Maurice CF, Kinnebrew MA, Abt MC, Schenten D, Golovkina TV, Bogatyrev SR, Ismagilov RF, Pamer EG, Turnbaugh PJ, Chervonsky AV - Nature (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA.

ABSTRACT
Systemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. 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). 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.

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MyD88-dependent pathway for fucosylation of SI IECs in response to systemic stimulation of TLRsa, FACS analysis of IECs from three segments of small intestine from the indicated mice. Cells are gated on the FSC/SSC high epithelial cell population. At least 2 mice per mutant genotype were stained along with two control mice in the experiments shown.b, SPF mice were pretreated with 20 mg streptomycin and orally infected with Salmonella typhimurium. SI was stained at 24 hours p.i. MyD88 expression was necessary in CD11c+ cells but not villin+ IECs for S. typhimurium-induced fucosylation.
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Figure 6: MyD88-dependent pathway for fucosylation of SI IECs in response to systemic stimulation of TLRsa, FACS analysis of IECs from three segments of small intestine from the indicated mice. Cells are gated on the FSC/SSC high epithelial cell population. At least 2 mice per mutant genotype were stained along with two control mice in the experiments shown.b, SPF mice were pretreated with 20 mg streptomycin and orally infected with Salmonella typhimurium. SI was stained at 24 hours p.i. MyD88 expression was necessary in CD11c+ cells but not villin+ IECs for S. typhimurium-induced fucosylation.

Mentions: Global deletion of the TLR signaling adaptor molecule MyD88 prevented IEC fucosylation and its conditional deletion from dendritic cells (DCs), but not IECs, abrogated the process (Fig. 1). The inducible fucosylation pathway was similar to induction of anti-microbial peptides by a systemic microbial signal15: it required MyD88-expressing DCs, production of IL-23, the transcriptional regulator RORγt and IL-22 (Fig. 1, Extended Data Fig. 2a), and was induced by a direct injection of IL-22 into MyD88−/− mice (Fig. 1). IEC fucosylation in mice lacking T cells (Fig. 1) suggested that ILCs were a sufficient source of IL-22. Salmonella enterica subsp.Typhimurium, known to spread systemically, induced SI IEC fucosylation (Extended Data Fig. 2b). The α(1,2)fucosyltransferase responsible for fucosylation of IECs in SI was identified as fucosyltransferase 2 (Fut2) (Fig. 2a), inducible by stress conditions16,17 and constitutively expressed in the stomach and large intestine18. Genetic ablation of the Fut2 gene blocked IEC fucosylation in response to LPS (Fig. 2b, c). The overall chain of events is shown in Extended Data Fig. 3.


Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness.

Pickard JM, Maurice CF, Kinnebrew MA, Abt MC, Schenten D, Golovkina TV, Bogatyrev SR, Ismagilov RF, Pamer EG, Turnbaugh PJ, Chervonsky AV - Nature (2014)

MyD88-dependent pathway for fucosylation of SI IECs in response to systemic stimulation of TLRsa, FACS analysis of IECs from three segments of small intestine from the indicated mice. Cells are gated on the FSC/SSC high epithelial cell population. At least 2 mice per mutant genotype were stained along with two control mice in the experiments shown.b, SPF mice were pretreated with 20 mg streptomycin and orally infected with Salmonella typhimurium. SI was stained at 24 hours p.i. MyD88 expression was necessary in CD11c+ cells but not villin+ IECs for S. typhimurium-induced fucosylation.
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Related In: Results  -  Collection

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Figure 6: MyD88-dependent pathway for fucosylation of SI IECs in response to systemic stimulation of TLRsa, FACS analysis of IECs from three segments of small intestine from the indicated mice. Cells are gated on the FSC/SSC high epithelial cell population. At least 2 mice per mutant genotype were stained along with two control mice in the experiments shown.b, SPF mice were pretreated with 20 mg streptomycin and orally infected with Salmonella typhimurium. SI was stained at 24 hours p.i. MyD88 expression was necessary in CD11c+ cells but not villin+ IECs for S. typhimurium-induced fucosylation.
Mentions: Global deletion of the TLR signaling adaptor molecule MyD88 prevented IEC fucosylation and its conditional deletion from dendritic cells (DCs), but not IECs, abrogated the process (Fig. 1). The inducible fucosylation pathway was similar to induction of anti-microbial peptides by a systemic microbial signal15: it required MyD88-expressing DCs, production of IL-23, the transcriptional regulator RORγt and IL-22 (Fig. 1, Extended Data Fig. 2a), and was induced by a direct injection of IL-22 into MyD88−/− mice (Fig. 1). IEC fucosylation in mice lacking T cells (Fig. 1) suggested that ILCs were a sufficient source of IL-22. Salmonella enterica subsp.Typhimurium, known to spread systemically, induced SI IEC fucosylation (Extended Data Fig. 2b). The α(1,2)fucosyltransferase responsible for fucosylation of IECs in SI was identified as fucosyltransferase 2 (Fut2) (Fig. 2a), inducible by stress conditions16,17 and constitutively expressed in the stomach and large intestine18. Genetic ablation of the Fut2 gene blocked IEC fucosylation in response to LPS (Fig. 2b, c). The overall chain of events is shown in Extended Data Fig. 3.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA.

ABSTRACT
Systemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. 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). 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.

Show MeSH
Related in: MedlinePlus