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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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Effect of exogenous fucose on cecal short-chain fatty acid (SCFA) levels. Cecal SCFAs were measured after gavaging starved mice with the indicated sugars (100 mM concentration). Fucose gavage leads to increased propionate production in SPF but not GF mice. Means±s.e.m.; **P<0.01, Student's two-tailed t test.
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Figure 13: Effect of exogenous fucose on cecal short-chain fatty acid (SCFA) levels. Cecal SCFAs were measured after gavaging starved mice with the indicated sugars (100 mM concentration). Fucose gavage leads to increased propionate production in SPF but not GF mice. Means±s.e.m.; **P<0.01, Student's two-tailed t test.

Mentions: Thus, inducible IEC fucosylation might be viewed as an emergency measure taken by the host to support the gut commensals. Fucose used by microbes as an energy source may contribute to protection of the host from endogenous opportunistic pathogens, or it could increase tolerance of infection by regulating bacterial genes responsible for quorum sensing26 or virulence27. Fucose can also serve as a substrate for microbial production of the short chain fatty acid propionate (Extended Data Fig. 9), which is primarily produced by members of the Bacteroidetes phylum28. Whether this process contributes to overall fitness of the animals under infection-induced stress remains to be elucidated. Of note, around 20% of humans lack a functional FUT2 gene, which is linked to Crohn's disease29 and to lethality from sepsis in premature infants30. Overall, fucosylation of SI in response to systemic microbial exposure can be considered a type of ‘tolerance of infection’ response. It is interesting, however, that a very similar pathway regulates secretion of antimicrobial proteins - a resistance mechanism15. Thus, the mechanisms of resistance and tolerance to pathogens could be evolutionarily linked to increase the fitness of the host.


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)

Effect of exogenous fucose on cecal short-chain fatty acid (SCFA) levels. Cecal SCFAs were measured after gavaging starved mice with the indicated sugars (100 mM concentration). Fucose gavage leads to increased propionate production in SPF but not GF mice. Means±s.e.m.; **P<0.01, Student's two-tailed t test.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 13: Effect of exogenous fucose on cecal short-chain fatty acid (SCFA) levels. Cecal SCFAs were measured after gavaging starved mice with the indicated sugars (100 mM concentration). Fucose gavage leads to increased propionate production in SPF but not GF mice. Means±s.e.m.; **P<0.01, Student's two-tailed t test.
Mentions: Thus, inducible IEC fucosylation might be viewed as an emergency measure taken by the host to support the gut commensals. Fucose used by microbes as an energy source may contribute to protection of the host from endogenous opportunistic pathogens, or it could increase tolerance of infection by regulating bacterial genes responsible for quorum sensing26 or virulence27. Fucose can also serve as a substrate for microbial production of the short chain fatty acid propionate (Extended Data Fig. 9), which is primarily produced by members of the Bacteroidetes phylum28. Whether this process contributes to overall fitness of the animals under infection-induced stress remains to be elucidated. Of note, around 20% of humans lack a functional FUT2 gene, which is linked to Crohn's disease29 and to lethality from sepsis in premature infants30. Overall, fucosylation of SI in response to systemic microbial exposure can be considered a type of ‘tolerance of infection’ response. It is interesting, however, that a very similar pathway regulates secretion of antimicrobial proteins - a resistance mechanism15. Thus, the mechanisms of resistance and tolerance to pathogens could be evolutionarily linked to increase the fitness of the host.

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