Letter | Published:

Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens

Nature volume 502, pages 9699 (03 October 2013) | Download Citation

Subjects

Abstract

The human intestine, colonized by a dense community of resident microbes, is a frequent target of bacterial pathogens. Undisturbed, this intestinal microbiota provides protection from bacterial infections. Conversely, disruption of the microbiota with oral antibiotics often precedes the emergence of several enteric pathogens1,2,3,4. How pathogens capitalize upon the failure of microbiota-afforded protection is largely unknown. Here we show that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium (S. typhimurium) and Clostridium difficile, use a common strategy of catabolizing microbiota-liberated mucosal carbohydrates during their expansion within the gut. S. typhimurium accesses fucose and sialic acid within the lumen of the gut in a microbiota-dependent manner, and genetic ablation of the respective catabolic pathways reduces its competitiveness in vivo. Similarly, C. difficile expansion is aided by microbiota-induced elevation of sialic acid levels in vivo. Colonization of gnotobiotic mice with a sialidase-deficient mutant of Bacteroides thetaiotaomicron, a model gut symbiont, reduces free sialic acid levels resulting in C. difficile downregulating its sialic acid catabolic pathway and exhibiting impaired expansion. These effects are reversed by exogenous dietary administration of free sialic acid. Furthermore, antibiotic treatment of conventional mice induces a spike in free sialic acid and mutants of both Salmonella and C. difficile that are unable to catabolize sialic acid exhibit impaired expansion. These data show that antibiotic-induced disruption of the resident microbiota and subsequent alteration in mucosal carbohydrate availability are exploited by these two distantly related enteric pathogens in a similar manner. This insight suggests new therapeutic approaches for preventing diseases caused by antibiotic-associated pathogens.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

European Nucleotide Archive

Data deposits

Microbiota enumeration (16S rRNA) datasets have been deposited in the EMBL European Nucleotide Archive (ENA) under accession number ERP003629 and can also be found in the QIIME Database under the study ID 1958 (http://www.microbio.me/qiime/). Gene Chip datasets are available in the GEO database under accession number GSE49076.

References

  1. 1.

    , , , & Risk factors for Salmonella Enteritidis and Typhimurium (DT104 and non-DT104) infections in The Netherlands: predominant roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol. Infect. 134, 617–626 (2006)

  2. 2.

    et al. Epidemiologic evidence that prior antimicrobial exposure decreases resistance to infection by antimicrobial-sensitive Salmonella. J. Infect. Dis. 161, 255–260 (1990)

  3. 3.

    et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin. Infect. Dis. 41, 1254–1260 (2005)

  4. 4.

    , & Clostridium difficile colitis. N. Engl. J. Med. 330, 257–262 (1994)

  5. 5.

    , , , & Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005)

  6. 6.

    et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010)

  7. 7.

    et al. Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathog. 6, e1000711 (2010)

  8. 8.

    et al. Carbon nutrition of Escherichia coli in the mouse intestine. Proc. Natl Acad. Sci. USA 101, 7427–7432 (2004)

  9. 9.

    et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005)

  10. 10.

    , & Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4, 447–457 (2008)

  11. 11.

    et al. Comparison of carbon nutrition for pathogenic and commensal Escherichia coli strains in the mouse intestine. Infect. Immun. 76, 1143–1152 (2008)

  12. 12.

    et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012)

  13. 13.

    et al. Fucose sensing regulates bacterial intestinal colonization. Nature 492, 113–117 (2012)

  14. 14.

    , , , & Nutritional basis for colonization resistance by human commensal Escherichia coli strains HS and Nissle 1917 against E. coli O157:H7 in the mouse intestine. PLoS ONE 8, e53957 (2013)

  15. 15.

    , , & The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6, e280 (2008)

  16. 16.

    & A mouse model for S. typhimurium-induced enterocolitis. Trends Microbiol. 13, 497–503 (2005)

  17. 17.

    et al. Host transmission of Salmonella enterica serovar Typhimurium is controlled by virulence factors and indigenous intestinal microbiota. Infect. Immun. 76, 403–416 (2008)

  18. 18.

    et al. Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infect. Immun. 77, 3661–3669 (2009)

  19. 19.

    et al. A mouse model of Clostridium difficile-associated disease. Gastroenterology 135, 1984–1992 (2008)

  20. 20.

    , , & Diversity of microbial sialic acid metabolism. Microbiol. Mol. Biol. Rev. 68, 132–153 (2004)

  21. 21.

    et al. Consumption of human milk oligosaccharides by gut-related microbes. J. Agric. Food Chem. 58, 5334–5340 (2010)

  22. 22.

    , , & Cloning, sequencing and distribution of the Salmonella typhimurium LT2 sialidase gene, nanH, provides evidence for interspecies gene transfer. Mol. Microbiol. 6, 873–884 (1992)

  23. 23.

    et al. The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nature Genet. 38, 779–786 (2006)

  24. 24.

    et al. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, e244 (2007)

  25. 25.

    et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010)

  26. 26.

    et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007)

  27. 27.

    et al. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect. Immun. 76, 907–915 (2008)

  28. 28.

    & One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl Acad. Sci. USA 97, 6640–6645 (2000)

  29. 29.

    & Identification of an inducible catabolic system for sialic acids (nan) in Escherichia coli. J. Bacteriol. 164, 845–853 (1985)

  30. 30.

    et al. The ClosTron: mutagenesis in Clostridium refined and streamlined. J. Microbiol. Methods 80, 49–55 (2010)

  31. 31.

    et al. Structural and functional studies of the CspB protease required for Clostridium spore germination. PLoS Pathog. 9, e1003165 (2013)

  32. 32.

    et al. Construction and analysis of chromosomal Clostridium difficile mutants. Mol. Microbiol. 61, 1335–1351 (2006)

  33. 33.

    et al. Specificity of polysaccharide use in intestinal bacteroides species determines diet-induced microbiota alterations. Cell 141, 1241–1252 (2010)

  34. 34.

    et al. Statistical issues in the normalization of multi-species microarray data. Appl. Stat. Agric. Proc. Conf. Appl. Stat. Agric. Kansas State Univ. 47–62 (National Agricultural Library, 2008)

  35. 35.

    , & Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

  36. 36.

    , & High-pressure liquid chromatography of sialic acids on a pellicular resin anion-exchange column with pulsed amperometric detection: a comparison with six other systems. Anal. Biochem. 188, 20–32 (1990)

  37. 37.

    et al. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. 6, 1621–1624 (2012)

  38. 38.

    et al. QIIME allows analysis of high-throughput community sequencing data. Nature Methods 7, 335–336 (2010)

  39. 39.

    , & UniFrac–an online tool for comparing microbial community diversity in a phylogenetic context. BMC Bioinformatics 7, 371 (2006)

Download references

Acknowledgements

We thank E. Sonnenburg for comments on the manuscript; M. St. Onge for technical assistance; and A. Shen, N. Minton and R. Knight for valuable help and reagents. This research was supported by R01-DK085025 (to J.L.S.), NSF graduate fellowships (to K.M.N. and J.A.F) and a Stanford Graduate Fellowship (to K.M.N.). J.L.S. holds an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund.

Author information

Author notes

    • Katharine M. Ng
    •  & Jessica A. Ferreyra

    These authors contributed equally to this work.

    • Purna C. Kashyap

    Present address: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.

Affiliations

  1. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Katharine M. Ng
    • , Jessica A. Ferreyra
    • , Steven K. Higginbottom
    • , Jonathan B. Lynch
    • , Purna C. Kashyap
    • , Smita Gopinath
    • , Denise M. Monack
    •  & Justin L. Sonnenburg
  2. Glycobiology Research and Training Center, University of California, San Diego, California 92093, USA

    • Natasha Naidu
    •  & Biswa Choudhury
  3. Department of Population Health and Reproduction, University of California, Davis, California 95616, USA

    • Bart C. Weimer

Authors

  1. Search for Katharine M. Ng in:

  2. Search for Jessica A. Ferreyra in:

  3. Search for Steven K. Higginbottom in:

  4. Search for Jonathan B. Lynch in:

  5. Search for Purna C. Kashyap in:

  6. Search for Smita Gopinath in:

  7. Search for Natasha Naidu in:

  8. Search for Biswa Choudhury in:

  9. Search for Bart C. Weimer in:

  10. Search for Denise M. Monack in:

  11. Search for Justin L. Sonnenburg in:

Contributions

K.M.N., J.A.F., D.M.M. and J.L.S. designed experiments. K.M.N., J.A.F., S.K.H., J.B.L., P.C.K., N.N., B.C. and J.L.S. performed experiments. K.M.N., J.A.F., P.C.K., S.G., N.N., D.M.M. and J.L.S. analysed data. D.M.M. and B.C.W. contributed reagents. K.M.N., J.A.F. and J.L.S. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Justin L. Sonnenburg.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    This file contains Supplementary Figures 1-11 and Supplementary Tables 1-3.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature12503

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.