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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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Microbial community structure is impacted by co-housing yet robust to host fucosylation and LPS exposure, whereas microbial gene expression depends on Fut2a, Stable relative abundance of bacterial phyla across treatment groups and genotypes, as indicated by 16S rRNA gene sequencing. Values represent the mean abundance of phyla found at >1% relative abundance in at least one sample.b, Unweighted UniFrac analysis of the gut microbiota of Fut2-deficient (no outline) and Fut2-sufficient (black outline) mice. Points are colored based on kinship and labeled by timepoint (before or after LPS exposure). Results are based on 180,000 randomly selected 16S rRNA gene sequences/sample.c, Microbial diversity as measured by the Shannon Diversity Index (n = 178,100 sequences/sample). Values are mean±s.e.m. (n = 3 Fut2+, 4 Fut2− mice/timepoint).d, KEGG modules and pathways expressed in microbiota at higher levels after LPS exposure in Fut2-positive (left) and Fut2-negative mice (right) (n = 3/group; Humann/LefSe analysis; LDA>2).
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Figure 11: Microbial community structure is impacted by co-housing yet robust to host fucosylation and LPS exposure, whereas microbial gene expression depends on Fut2a, Stable relative abundance of bacterial phyla across treatment groups and genotypes, as indicated by 16S rRNA gene sequencing. Values represent the mean abundance of phyla found at >1% relative abundance in at least one sample.b, Unweighted UniFrac analysis of the gut microbiota of Fut2-deficient (no outline) and Fut2-sufficient (black outline) mice. Points are colored based on kinship and labeled by timepoint (before or after LPS exposure). Results are based on 180,000 randomly selected 16S rRNA gene sequences/sample.c, Microbial diversity as measured by the Shannon Diversity Index (n = 178,100 sequences/sample). Values are mean±s.e.m. (n = 3 Fut2+, 4 Fut2− mice/timepoint).d, KEGG modules and pathways expressed in microbiota at higher levels after LPS exposure in Fut2-positive (left) and Fut2-negative mice (right) (n = 3/group; Humann/LefSe analysis; LDA>2).

Mentions: To confirm these findings in mice with a complex gut microbiota, we profiled microbial community structure, gene abundance, and transcriptional activity before and after LPS treatment of Fut2+/− and Fut2−/− mice (Supplemental Information Table 1). Analyses of community structure based on 16S and shotgun DNA sequencing revealed that the gut microbiota was largely robust to host genotype and LPS exposure (Fig. 3g, Extended Data Fig. 7a,b). We did not detect (a) significant clustering of microbial communities based on genotype or LPS treatment [P>0.05 for both comparisons; permutational multivariate analysis of variance (PERMANOVA) of unweighted UniFrac distances]; (b) species-level operational taxonomic units (OTUs) significantly associated with host genotype prior to or following LPS treatment (all were q>0.05; ANOVA); or (c) significant differences in overall microbial diversity (Extended Data Fig. 7c). However, we were able to detect a significantly increased abundance of B. acidifaciens following LPS treatment in Fut2-sufficient mice (P<0.05, LDA score>4; LefSe analysis of 16S profiles), consistent with its ability to utilize fucosylated glycans. At the same time, LPS markedly altered community-wide gene expression in both Fut2+/− and Fut2−/− mice (Fig. 3h) with multiple orthologous groups differentially expressed upon LPS treatment: 61 in Fut2+/− mice and 56 in Fut2−/− animals. These changes were not due to altered community structure: only 1 differentially expressed orthologous group (K05351, xylulose reductase) also exhibited significant changes in gene abundance (Supplemental Information Table 2). As expected, we detected a significant upregulation of fucose permease (fucP; K02429) in Fut2-sufficient mice after exposure to LPS (Fig. 3i), and increased expression of metabolic modules for anaerobic respiration, protein and ATP synthesis, isoprenoid biosynthesis, and amino sugar import, in addition to pathways for aminoglycan degradation (Extended Data Fig. 7d). Thus, intact host fucosylation appears to affect gut microbial metabolism.


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)

Microbial community structure is impacted by co-housing yet robust to host fucosylation and LPS exposure, whereas microbial gene expression depends on Fut2a, Stable relative abundance of bacterial phyla across treatment groups and genotypes, as indicated by 16S rRNA gene sequencing. Values represent the mean abundance of phyla found at >1% relative abundance in at least one sample.b, Unweighted UniFrac analysis of the gut microbiota of Fut2-deficient (no outline) and Fut2-sufficient (black outline) mice. Points are colored based on kinship and labeled by timepoint (before or after LPS exposure). Results are based on 180,000 randomly selected 16S rRNA gene sequences/sample.c, Microbial diversity as measured by the Shannon Diversity Index (n = 178,100 sequences/sample). Values are mean±s.e.m. (n = 3 Fut2+, 4 Fut2− mice/timepoint).d, KEGG modules and pathways expressed in microbiota at higher levels after LPS exposure in Fut2-positive (left) and Fut2-negative mice (right) (n = 3/group; Humann/LefSe analysis; LDA>2).
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Figure 11: Microbial community structure is impacted by co-housing yet robust to host fucosylation and LPS exposure, whereas microbial gene expression depends on Fut2a, Stable relative abundance of bacterial phyla across treatment groups and genotypes, as indicated by 16S rRNA gene sequencing. Values represent the mean abundance of phyla found at >1% relative abundance in at least one sample.b, Unweighted UniFrac analysis of the gut microbiota of Fut2-deficient (no outline) and Fut2-sufficient (black outline) mice. Points are colored based on kinship and labeled by timepoint (before or after LPS exposure). Results are based on 180,000 randomly selected 16S rRNA gene sequences/sample.c, Microbial diversity as measured by the Shannon Diversity Index (n = 178,100 sequences/sample). Values are mean±s.e.m. (n = 3 Fut2+, 4 Fut2− mice/timepoint).d, KEGG modules and pathways expressed in microbiota at higher levels after LPS exposure in Fut2-positive (left) and Fut2-negative mice (right) (n = 3/group; Humann/LefSe analysis; LDA>2).
Mentions: To confirm these findings in mice with a complex gut microbiota, we profiled microbial community structure, gene abundance, and transcriptional activity before and after LPS treatment of Fut2+/− and Fut2−/− mice (Supplemental Information Table 1). Analyses of community structure based on 16S and shotgun DNA sequencing revealed that the gut microbiota was largely robust to host genotype and LPS exposure (Fig. 3g, Extended Data Fig. 7a,b). We did not detect (a) significant clustering of microbial communities based on genotype or LPS treatment [P>0.05 for both comparisons; permutational multivariate analysis of variance (PERMANOVA) of unweighted UniFrac distances]; (b) species-level operational taxonomic units (OTUs) significantly associated with host genotype prior to or following LPS treatment (all were q>0.05; ANOVA); or (c) significant differences in overall microbial diversity (Extended Data Fig. 7c). However, we were able to detect a significantly increased abundance of B. acidifaciens following LPS treatment in Fut2-sufficient mice (P<0.05, LDA score>4; LefSe analysis of 16S profiles), consistent with its ability to utilize fucosylated glycans. At the same time, LPS markedly altered community-wide gene expression in both Fut2+/− and Fut2−/− mice (Fig. 3h) with multiple orthologous groups differentially expressed upon LPS treatment: 61 in Fut2+/− mice and 56 in Fut2−/− animals. These changes were not due to altered community structure: only 1 differentially expressed orthologous group (K05351, xylulose reductase) also exhibited significant changes in gene abundance (Supplemental Information Table 2). As expected, we detected a significant upregulation of fucose permease (fucP; K02429) in Fut2-sufficient mice after exposure to LPS (Fig. 3i), and increased expression of metabolic modules for anaerobic respiration, protein and ATP synthesis, isoprenoid biosynthesis, and amino sugar import, in addition to pathways for aminoglycan degradation (Extended Data Fig. 7d). Thus, intact host fucosylation appears to affect gut microbial metabolism.

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