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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 fucosylation of SI IECs by systemic stimulation of TLRsAll panels: Ulex europaeus Agglutinin 1(UEA-1, binds α(1,2)-fucosylated substrates) staining in the proximal 1/3 of SI of mice untreated or 24 hours after i.p. LPS injection, or 6 hours after injection of IL-22 (MyD88−/− mouse). Scale bars=100 μm. Staining of tissue from mutant mice was always accompanied by staining of wild-type controls, and is representative of at least two independent experiments for each genotype.
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Figure 1: MyD88-dependent fucosylation of SI IECs by systemic stimulation of TLRsAll panels: Ulex europaeus Agglutinin 1(UEA-1, binds α(1,2)-fucosylated substrates) staining in the proximal 1/3 of SI of mice untreated or 24 hours after i.p. LPS injection, or 6 hours after injection of IL-22 (MyD88−/− mouse). Scale bars=100 μm. Staining of tissue from mutant mice was always accompanied by staining of wild-type controls, and is representative of at least two independent experiments for each genotype.

Mentions: To maintain the healthy gut microbiota during a systemic response induced by microbial products the host may use its internal resources. L-fucosylation could present an example of such a resource: L-fucose attached to glycoproteins and glycolipids is accessible for microbial, but not for host energy harvest7,8. Constitutive α(1,2)fucosylation affects microbial community in a diet-dependent manner9, serves as a substrate for pathogens during antibiotic exposure10 and for microbes colonizing the ileum of newborns or adult germ-free (GF) animals11-13. Under normal conditions, however, the small intestine (SI) of specific pathogen-free (SPF) BALB/c mice is largely free of surface fucose. In contrast, a systemic injection of agonists of Toll-like receptors (TLRs) such as lipopolysaccharide (LPS, TLR4 ligand) (Fig. 1), CpG DNA (TLR9 ligand), or Pam3CSK4 (TLR2 agonist), led to ubiquitous α(1,2)fucosylation of the SI in mice of different genetic backgrounds, which started within a few hours after LPS exposure and lasted several days (Extended Data Fig.1a-c). It did not result in differentiation of IECs into functional M cells 14 that are permanently fucosylated and are involved in microbial sensing and translocation (Extended Data Fig. 1d). Induced fucosylation was independent of the gut microbiota (observed in GF mice), and was not induced by oral LPS (Extended Data Fig. 1e).


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 fucosylation of SI IECs by systemic stimulation of TLRsAll panels: Ulex europaeus Agglutinin 1(UEA-1, binds α(1,2)-fucosylated substrates) staining in the proximal 1/3 of SI of mice untreated or 24 hours after i.p. LPS injection, or 6 hours after injection of IL-22 (MyD88−/− mouse). Scale bars=100 μm. Staining of tissue from mutant mice was always accompanied by staining of wild-type controls, and is representative of at least two independent experiments for each genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4214913&req=5

Figure 1: MyD88-dependent fucosylation of SI IECs by systemic stimulation of TLRsAll panels: Ulex europaeus Agglutinin 1(UEA-1, binds α(1,2)-fucosylated substrates) staining in the proximal 1/3 of SI of mice untreated or 24 hours after i.p. LPS injection, or 6 hours after injection of IL-22 (MyD88−/− mouse). Scale bars=100 μm. Staining of tissue from mutant mice was always accompanied by staining of wild-type controls, and is representative of at least two independent experiments for each genotype.
Mentions: To maintain the healthy gut microbiota during a systemic response induced by microbial products the host may use its internal resources. L-fucosylation could present an example of such a resource: L-fucose attached to glycoproteins and glycolipids is accessible for microbial, but not for host energy harvest7,8. Constitutive α(1,2)fucosylation affects microbial community in a diet-dependent manner9, serves as a substrate for pathogens during antibiotic exposure10 and for microbes colonizing the ileum of newborns or adult germ-free (GF) animals11-13. Under normal conditions, however, the small intestine (SI) of specific pathogen-free (SPF) BALB/c mice is largely free of surface fucose. In contrast, a systemic injection of agonists of Toll-like receptors (TLRs) such as lipopolysaccharide (LPS, TLR4 ligand) (Fig. 1), CpG DNA (TLR9 ligand), or Pam3CSK4 (TLR2 agonist), led to ubiquitous α(1,2)fucosylation of the SI in mice of different genetic backgrounds, which started within a few hours after LPS exposure and lasted several days (Extended Data Fig.1a-c). It did not result in differentiation of IECs into functional M cells 14 that are permanently fucosylated and are involved in microbial sensing and translocation (Extended Data Fig. 1d). Induced fucosylation was independent of the gut microbiota (observed in GF mice), and was not induced by oral LPS (Extended Data Fig. 1e).

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