Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

How glycan metabolism shapes the human gut microbiota

Key Points

  • The degradation of complex carbohydrates (glycans and polysaccharides) is a major symbiotic function carried out by microorganisms that inhabit the human distal gut. These mutualistic species augment host nutrition by digesting glycans that the host cannot degrade, providing the host with usable metabolic products such as short-chain fatty acids.

  • Hundreds of different glycan structures enter the gut from dietary and endogenous sources. Endogenous sources include glycans from host mucus and shed host cells. The 103 species of microorganism that typically inhabit the human gut have evolved varying abilities to degrade these different substrates.

  • The type and abundance of glycans that are present in the gut change over long time periods. For example, human milk oligosaccharides are abundant before weaning, but they wane after weaning in favour of plant and animal tissue-based glycans.

  • The chemical identities of glycans that enter the gut also vary over short time periods, essentially from meal to meal. Variations in the foods we eat can affect the abundance of different microbial populations, leading to more profound population changes over time if dietary trends are consistent.

  • Different bacterial lineages that have evolved to be successful gut colonizers possess different strategies for glycan degradation. One such strategy is the starch utilization system (Sus)-like systems of members of the phylum Bacteroidetes, in which a series of outer-membrane and periplasmic proteins act together to bind, enzymatically degrade and import glycan products.

  • Other abundant bacterial lineages, such as the phyla Firmicutes and Actinobacteria, possess different glycan acquisition strategies that also involve glycan-degrading enzymes. In both of these Gram-positive lineages, the coupling of degradative enzymes to ABC (ATP-binding cassette) transporters seems to be a successful adaptation. Sequence-based analyses have also suggested that cellulosomes are present in some bacteria which inhabit the human gut.

  • Various host and dietary glycans are unlikely to be represented homogeneously throughout the gut. One example of this phenomenon is the presence of mucus glycans in a protective layer overlying the intestinal epithelium; this layer increases in thickness along the gut to the distal end.

  • Some species that have evolved to exploit mucus glycans as nutrients are present in higher numbers in the mucous layer than the lumen, suggesting that they are particularly important in the pathology of microbiota-associated diseases such as inflammatory bowel disease.

Abstract

Symbiotic microorganisms that reside in the human intestine are adept at foraging glycans and polysaccharides, including those in dietary plants (starch, hemicellulose and pectin), animal-derived cartilage and tissue (glycosaminoglycans and N-linked glycans), and host mucus (O-linked glycans). Fluctuations in the abundance of dietary and endogenous glycans, combined with the immense chemical variation among these molecules, create a dynamic and heterogeneous environment in which gut microorganisms proliferate. In this Review, we describe how glycans shape the composition of the gut microbiota over various periods of time, the mechanisms by which individual microorganisms degrade these glycans, and potential opportunities to intentionally influence this ecosystem for better health and nutrition.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sources and chemical variation of glycans in the gut.
Figure 2: Variations in functional complexity among starch utilization system (Sus)-like systems.
Figure 3: Glycan utilization along the length of the human gut and its potential health effects.
Figure 4: Glycan microhabitats and food chains in the gut.

Similar content being viewed by others

References

  1. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009).

    Article  CAS  Google Scholar 

  2. Flint, H. J., Bayer, E. A., Rincon, M. T., Lamed, R. & White, B. A. Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis. Nature Rev. Microbiol. 6, 121–131 (2008).

    Article  CAS  Google Scholar 

  3. Wardwell, L. H., Huttenhower, C. & Garrett, W. S. Current concepts of the intestinal microbiota and the pathogenesis of infection. Curr. Infect. Dis. Rep. 13, 28–34 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Packey, C. D. & Sartor, R. B. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr. Opin. Infect. Dis. 22, 292–301 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  5. O'Keefe, S. J. et al. Products of the colonic microbiota mediate the effects of diet on colon cancer risk. J. Nutr. 139, 2044–2048 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Khoruts, A., Dicksved, J., Jansson, J. K. & Sadowsky, M. J. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J. Clin. Gastroenterol. 44, 354–360 (2010).

    PubMed  Google Scholar 

  7. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Sun, L., Nava, G. M. & Stappenbeck, T. S. Host genetic susceptibility, dysbiosis, and viral triggers in inflammatory bowel disease. Curr. Opin. Gastroenterol. 27, 321–327 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Garrett, W. S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bloom, S. M. et al. Commensal bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9, 390–403 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Turnbaugh, P. J. et al. Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc. Natl Acad. Sci. USA 107, 7503–7508 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011). A metagenomics-based analysis of a total of 272 new and published human faecal microbiomes, revealing the existence of just three dominant enterotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Caporaso, J. G. et al. Moving pictures of the human microbiome. Genome Biol. 12, R50 (2011). The first long-term study of the dynamics of the human faecal microbiome, with a daily time point analysis.

    Article  PubMed  PubMed Central  Google Scholar 

  16. McNeil, N. I. The contribution of the large intestine to energy supplies in man. Am. J. Clin. Nutr. 39, 338–342 (1984).

    Article  CAS  PubMed  Google Scholar 

  17. Salyers, A. A., Vercellotti, J. R., West, S. E. & Wilkins, T. D. Fermentation of mucin and plant polysaccharides by strains of Bacteroides from the human colon. Appl. Environ. Microbiol. 33, 319–322 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Salyers, A. A., West, S. E., Vercellotti, J. R. & Wilkins, T. D. Fermentation of mucins and plant polysaccharides by anaerobic bacteria from the human colon. Appl. Environ. Microbiol. 34, 529–533 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Marcobal, A. et al. Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways. Cell Host Microbe 10, 507–514 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mohnen, D. Pectin structure and biosynthesis. Curr. Opin. Plant Biol. 11, 266–277 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Saulnier, L., Marot, C., Chanliaud, E. & Thibault, J.-F. Cell wall polysaccharide interactions in maize bran. Carbohydr. Polym. 26, 279–287 (1995).

    Article  CAS  Google Scholar 

  22. Larsson, J. M., Karlsson, H., Sjovall, H. & Hansson, G. C. A complex, but uniform O-glycosylation of the human MUC2 mucin from colonic biopsies analyzed by nanoLC/MSn. Glycobiology 19, 756–766 (2009).

    Article  PubMed  CAS  Google Scholar 

  23. Hamer, H. M. et al. Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104–119 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Rombeau, J. L. & Kripke, S. A. Metabolic and intestinal effects of short-chain fatty acids. JPEN. J. Parenter. Enteral Nutr. 14, S181–S185 (1990).

    Article  Google Scholar 

  25. Duncan, S. H., Barcenilla, A., Stewart, C. S., Pryde, S. E. & Flint, H. J. Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl. Environ. Microbiol. 68, 5186–5190 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Duncan, S. H. et al. Contribution of acetate to butyrate formation by human faecal bacteria. Br. J. Nutr. 91, 915–923 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Palmer, C., Bik, E. M., Digiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177 (2007).

    PubMed  PubMed Central  Google Scholar 

  29. Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4578–4585 (2010). A study of microbiota formation in a single human child over the first 3 years of life, using 16S rRNA genes and metagenomic approaches to correlate changes in the microbiota with life events such as diet shifts, illness and antibiotics.

    PubMed  PubMed Central  Google Scholar 

  30. Kunz, C., Rudloff, S., Baier, W., Klein, N. & Strobel, S. Oligosaccharides in human milk: structural, functional, and metabolic aspects. Annu. Rev. Nutr. 20, 699–722 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Ninonuevo, M. R. et al. A strategy for annotating the human milk glycome. J. Agric. Food Chem. 54, 7471–7480 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Fuhrer, A. et al. Milk sialyllactose influences colitis in mice through selective intestinal bacterial colonization. J. Exp. Med. 207, 2843–2854 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chaturvedi, P., Warren, C. D., Buescher, C. R., Pickering, L. K. & Newburg, D. S. Survival of human milk oligosaccharides in the intestine of infants. Adv. Exp. Med. Biol. 501, 315–323 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. German, J. B., Freeman, S. L., Lebrilla, C. B. & Mills, D. A. Human milk oligosaccharides: evolution, structures and bioselectivity as substrates for intestinal bacteria. Nestle Nutr. Workshop Ser. Pediatr. Program 62, 205–218; discussion 218–222 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gnoth, M. J., Kunz, C., Kinne-Saffran, E. & Rudloff, S. Human milk oligosaccharides are minimally digested in vitro. J. Nutr. 130, 3014–3020 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Favier, C. F., Vaughan, E. E., De Vos, W. M. & Akkermans, A. D. Molecular monitoring of succession of bacterial communities in human neonates. Appl. Environ. Microbiol. 68, 219–226 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sela, D. A. Bifidobacterial utilization of human milk oligosaccharides. Int. J. Food Microbiol. 149, 58–64 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Miwa, M. et al. Cooperation of β-galactosidase and β-N-acetylhexosaminidase from bifidobacteria in assimilation of human milk oligosaccharides with type 2 structure. Glycobiology 20, 1402–1409 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. LoCascio, R. G., Desai, P., Sela, D. A., Weimer, B. & Mills, D. A. Broad conservation of milk utilization genes in Bifidobacterium longum subsp. infantis as revealed by comparative genomic hybridization. Appl. Environ. Microbiol. 76, 7373–7381 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Turroni, F. et al. Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging. Proc. Natl Acad. Sci. USA 107, 19514–19519 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Garrido, D., Kim, J. H., German, J. B., Raybould, H. E. & Mills, D. A. Oligosaccharide binding proteins from Bifidobacterium longum subsp. infantis reveal a preference for host glycans. PLoS ONE 6, e17315 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Martinez, R. C. et al. In vitro evaluation of gastrointestinal survival of Lactobacillus amylovorus DSM 16698 alone and combined with galactooligosaccharides, milk and/or Bifidobacterium animalis subsp. lactis Bb-12. Int. J. Food Microbiol. 149, 152–158 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Rodriguez-Diaz, J., Monedero, V. & Yebra, M. J. Utilization of natural fucosylated oligosaccharides by three novel α-L-fucosidases from a probiotic Lactobacillus casei strain. Appl. Environ. Microbiol. 77, 703–705 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Schwab, C. & Ganzle, M. Lactic acid bacteria fermentation of human milk oligosaccharide components, human milk oligosaccharides and galactooligosaccharides. FEMS Microbiol. Lett. 315, 141–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Coppa, G. V. et al. Oligosaccharides in human milk during different phases of lactation. Acta Paediatr. Suppl. 88, 89–94 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Favier, C. F., de Vos, W. M. & Akkermans, A. D. Development of bacterial and bifidobacterial communities in feces of newborn babies. Anaerobe 9, 219–229 (2003).

    Article  PubMed  Google Scholar 

  47. Fallani, M. et al. Determinants of the human infant intestinal microbiota after the introduction of first complementary foods in infant samples from five European centres. Microbiology 157, 1385–1392 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Harmsen, H. J. et al. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J. Pediatr. Gastroenterol. Nutr. 30, 61–67 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Kurokawa, K. et al. Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes. DNA Res. 14, 169–181 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mariat, D. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 9, 123 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005). The first in vivo transcriptomics-based study of a human gut symbiont ( B. thetaiotaomicron ) in the intestines of gnotobiotic mice consuming diets with varying glycan content.

    Article  CAS  PubMed  Google Scholar 

  52. Bjursell, M. K., Martens, E. C. & Gordon, J. I. Functional genomic and metabolic studies of the adaptations of a prominent adult human gut symbiont, Bacteroides thetaiotaomicron, to the suckling period. J. Biol. Chem. 281, 36269–36279 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Martens, E. C., Chiang, H. C. & Gordon, J. I. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4, 447–457 (2008). A study that uses transcriptional profiling of in vitro -grown cultures to identify B. thetaiotaomicron genes that are involved in the degradation of host glycans. This study demonstrates a link between foraging for host glycans and intergenerational transmission of microbiota members.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Franks, A. H. et al. Variations of bacterial populations in human feces measured by fluorescent in situ hybridization with group-specific 16S rRNA-targeted oligonucleotide probes. Appl. Environ. Microbiol. 64, 3336–3345 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Zoetendal, E. G., Akkermans, A. D. & De Vos, W. M. Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Appl. Environ. Microbiol. 64, 3854–3859 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hill, J. E. et al. Improvement of the representation of bifidobacteria in fecal microbiota metagenomic libraries by application of the cpn60 universal primer cocktail. Appl. Environ. Microbiol. 76, 4550–4552 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010). An investigation that analyses the composition of the microbiota in two populations of children (one in Africa and the other in Europe) that consume different diets.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Tap, J. et al. Towards the human intestinal microbiota phylogenetic core. Environ. Microbiol. 11, 2574–2584 (2009).

    Article  PubMed  Google Scholar 

  61. Meyer, D. & Stasse-Wolthuis, M. The bifidogenic effect of inulin and oligofructose and its consequences for gut health. Eur. J. Clin. Nutr. 63, 1277–1289 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Sonnenburg, E. D. et al. Specificity of polysaccharide use in intestinal Bacteroides species determines diet-induced microbiota alterations. Cell 141, 1241–1252 (2010). A mechanistic study of fructan utilization by multiple Bacteroides spp. from the human gut microbiota, revealing that a single gene cluster can be evolutionarily altered between species to switch glycan substrate specificity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Segain, J. P. et al. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn's disease. Gut 47, 397–403 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Luhrs, H. et al. Cytokine-activated degradation of inhibitory κB protein α is inhibited by the short-chain fatty acid butyrate. Int. J. Colorectal Dis. 16, 195–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Hamer, H. M. et al. Butyrate modulates oxidative stress in the colonic mucosa of healthy humans. Clin. Nutr. 28, 88–93 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Pryde, S. E., Duncan, S. H., Hold, G. L., Stewart, C. S. & Flint, H. J. The microbiology of butyrate formation in the human colon. FEMS Microbiol. Lett. 217, 133–139 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Avivi-Green, C., Polak-Charcon, S., Madar, Z. & Schwartz, B. Apoptosis cascade proteins are regulated in vivo by high intracolonic butyrate concentration: correlation with colon cancer inhibition. Oncol. Res. 12, 83–95 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. McIntyre, A., Gibson, P. R. & Young, G. P. Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gut 34, 386–391 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dronamraju, S. S., Coxhead, J. M., Kelly, S. B., Burn, J. & Mathers, J. C. Cell kinetics and gene expression changes in colorectal cancer patients given resistant starch: a randomised controlled trial. Gut 58, 413–420 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Clarke, J. M., Topping, D. L., Bird, A. R., Young, G. P. & Cobiac, L. Effects of high-amylose maize starch and butyrylated high-amylose maize starch on azoxymethane-induced intestinal cancer in rats. Carcinogenesis 29, 2190–2194 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Van Immerseel, F. et al. Butyric acid-producing anaerobic bacteria as a novel probiotic treatment approach for inflammatory bowel disease. J. Med. Microbiol. 59, 141–143 (2010).

    Article  PubMed  Google Scholar 

  72. Pan, N. & Imlay, J. A. How does oxygen inhibit central metabolism in the obligate anaerobe Bacteroides thetaiotaomicron. Mol. Microbiol. 39, 1562–1571 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Sakamoto, M. et al. Butyricimonas synergistica gen. nov., sp. nov. and Butyricimonas virosa sp. nov., butyric acid-producing bacteria in the family 'Porphyromonadaceae' isolated from rat faeces. Int. J. Syst. Evol. Microbiol. 59, 1748–1753 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Martinez, I., Kim, J., Duffy, P. R., Schlegel, V. L. & Walter, J. Resistant starches types 2 and 4 have differential effects on the composition of the fecal microbiota in human subjects. PLoS ONE 5, e15046 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2011). A human volunteer study that tracks the changes in the microbiota following a shift to a low-carbohydrate diet, then to an RS-containing diet and finally to a diet that is rich in non-starch polysaccharides.

    Article  CAS  PubMed  Google Scholar 

  76. McWilliam Leitch, E. C., Walker, A. W., Duncan, S. H., Holtrop, G. & Flint, H. J. Selective colonization of insoluble substrates by human faecal bacteria. Environ. Microbiol. 9, 667–679 (2007).

    Article  CAS  Google Scholar 

  77. Macfarlane, S. & Macfarlane, G. T. Composition and metabolic activities of bacterial biofilms colonizing food residues in the human gut. Appl. Environ. Microbiol. 72, 6204–6211 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009). An investigation that uses culture-independent methods to monitor alterations in the microbiota of humanized mice in response to rapid diet shift.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Faith, J. J., McNulty, N. P., Rey, F. E. & Gordon, J. I. Predicting a human gut microbiota's response to diet in gnotobiotic mice. Science 333, 101–104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Goodman, A. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl Acad. Sci. USA 108, 6252–6257 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mahowald, M. A. et al. Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proc. Natl Acad. Sci. USA 106, 5859–5864 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. D'Elia, J. N. & Salyers, A. A. Contribution of a neopullulanase, a pullulanase, and an α-glucosidase to growth of Bacteroides thetaiotaomicron on starch. J. Bacteriol. 178, 7173–7179 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cho, K. H. & Salyers, A. A. Biochemical analysis of interactions between outer membrane proteins that contribute to starch utilization by Bacteroides thetaiotaomicron. J. Bacteriol. 183, 7224–7230 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Xu, J. et al. Evolution of symbiotic bacteria in the distal human intestine. PLoS Biol. 5, e156 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Martens, E. C., Koropatkin, N. M., Smith, T. J. & Gordon, J. I. Complex glycan catabolism by the human gut microbiota: the Bacteroidetes Sus-like paradigm. J. Biol. Chem. 284, 24673–24677 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tancula, E., Feldhaus, M. J., Bedzyk, L. A. & Salyers, A. A. Location and characterization of genes involved in binding of starch to the surface of Bacteroides thetaiotaomicron. J. Bacteriol. 174, 5609–5616 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Xu, J. et al. A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Martens, E. C. et al. Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts. PLoS Biol. 9, e1001221 (2011). The first transcriptomic and genetic study to link specific genes in Bacteroides spp. from the human gut microbiota with degradation of all major plant cell wall polysaccharides except cellulose.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hehemann, J. H. et al. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464, 908–912 (2010). This work identifies an enzyme system that is involved in degrading a polysaccharide present in seaweed. This system was transferred from the marine metagenome to the human microbiome as a response to seaweed consumption.

    Article  CAS  PubMed  Google Scholar 

  91. Dodd, D., Moon, Y. H., Swaminathan, K., Mackie, R. I. & Cann, I. K. Transcriptomic analyses of xylan degradation by Prevotella bryantii and insights into energy acquisition by xylanolytic bacteroidetes. J. Biol. Chem. 285, 30261–30273 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Miyazaki, K., Hirase, T., Kojima, Y. & Flint, H. J. Medium- to large-sized xylo-oligosaccharides are responsible for xylanase induction in Prevotella bryantii B14. Microbiology 151, 4121–4125 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Bauer, M. et al. Whole genome analysis of the marine Bacteroidetes 'Gramella forsetii' reveals adaptations to degradation of polymeric organic matter. Environ. Microbiol. 8, 2201–2213 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. McBride, M. J. et al. Novel features of the polysaccharide-digesting gliding bacterium Flavobacterium johnsoniae revealed by genome sequence analysis. Appl. Environ. Microbiol. 75, 6864–6875 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Renzi, F. et al. The N-glycan glycoprotein deglycosylation complex (Gpd) from Capnocytophaga canimorsus deglycosylates human IgG. PLoS Pathog. 7, e1002118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Koropatkin, N. M. & Smith, T. J. SusG: a unique cell-membrane-associated α-amylase from a prominent human gut symbiont targets complex starch molecules. Structure 18, 200–215 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Koropatkin, N. M., Martens, E. C., Gordon, J. I. & Smith, T. J. Starch catabolism by a prominent human gut symbiont is directed by the recognition of amylose helices. Structure 16, 1105–1115 (2008). A report of the structure of SusD, the B. thetaiotaomicron starch-binding protein, revealing a novel fold and the site of glycan interaction in this broadly expanded family of bacteroidetes proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rey, F. E. et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082–22090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Fontes, C. M. & Gilbert, H. J. Cellulosomes: highly efficient nanomachines designed to deconstruct plant cell wall complex carbohydrates. Annu. Rev. Biochem. 79, 655–681 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Bayer, E. A., Lamed, R., White, B. A. & Flint, H. J. From cellulosomes to cellulosomics. Chem. Rec. 8, 364–377 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Pokusaeva, K., Fitzgerald, G. F. & van Sinderen, D. Carbohydrate metabolism in bifidobacteria. Genes Nutr. 6, 285–306 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Swidsinski, A., Loening-Baucke, V., Lochs, H. & Hale, L. P. Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J. Gastroenterol. 11, 1131–1140 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Huang, J. Y., Lee, S. M. & Mazmanian, S. K. The human commensal Bacteroides fragilis binds intestinal mucin. Anaerobe 17, 137–141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Macfarlane, G. T. & Gibson, G. R. Formation of glycoprotein degrading enzymes by Bacteroides fragilis. FEMS Microbiol. Lett. 61, 289–293 (1991).

    Article  CAS  PubMed  Google Scholar 

  105. Sonnenburg, J. L., Chen, C. T. & Gordon, J. I. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol. 4, e413 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Gibson, G. R. et al. Alternative pathways for hydrogen disposal during fermentation in the human colon. Gut 31, 679–683 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cantarel, B. L. et al. The Carbohydrate-Active EnZymes database (CAZy): an expert resource for glycogenomics. Nucleic Acids Res. 37, D233–D238 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Nelson, K. E. et al. A catalog of reference genomes from the human microbiome. Science 328, 994–999 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Zhang, G. & Hamaker, B. R. Slowly digestible starch: concept, mechanism, and proposed extended glycemic index. Crit. Rev. Food Sci. Nutr. 49, 852–867 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Englyst, H. N., Kingman, S. M. & Cummings, J. H. Classification and measurement of nutritionally important starch fractions. Eur. J. Clin. Nutr. 46 (Suppl. 2), S33–S50 (1992).

    PubMed  Google Scholar 

  111. Scott, K. P. et al. Substrate-driven gene expression in Roseburia inulinivorans: importance of inducible enzymes in the utilization of inulin and starch. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4672–4679 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Ramirez-Farias, C. et al. Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br. J. Nutr. 101, 541–550 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Cani, P. D. et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 50, 2374–2383 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Delzenne, N. M., Cani, P. D. & Neyrinck, A. M. Modulation of glucagon-like peptide 1 and energy metabolism by inulin and oligofructose: experimental data. J. Nutr. 137, S2547–S2551 (2007).

    Article  Google Scholar 

  115. Gourineni, V. P., Verghese, M., Boateng, J., Shackelford, L. & Bhat, K. N. Chemopreventive potential of synergy1 and soybean in reducing azoxymethane-induced aberrant crypt foci in fisher 344 male rats. J. Nutr. Metab. 2011, 983038 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Munjal, U., Glei, M., Pool-Zobel, B. L. & Scharlau, D. Fermentation products of inulin-type fructans reduce proliferation and induce apoptosis in human colon tumour cells of different stages of carcinogenesis. Br. J. Nutr. 102, 663–671 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Neyrinck, A. M. et al. Prebiotic effects of wheat arabinoxylan related to the increase in bifidobacteria, Roseburia and Bacteroides/Prevotella in diet-induced obese mice. PLoS ONE 6, e20944 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Neyrinck, A. M. et al. Dietary modulation of clostridial cluster XIVa gut bacteria (Roseburia spp.) by chitin–glucan fiber improves host metabolic alterations induced by high-fat diet in mice. J. Nutr. Biochem. 23, 51–59 (2011).

    Article  PubMed  CAS  Google Scholar 

  119. Van den Abbeele, P. et al. Arabinoxylans and inulin differentially modulate the mucosal and luminal gut microbiota and mucin-degradation in humanized rats. Environ. Microbiol. 13, 2667–2680 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Varki, A. et al. Essentials of Glycobiology (Cold Spring Harbor Lab. Press, 1999).

    Google Scholar 

  121. Matsuo, K., Ota, H., Akamatsu, T., Sugiyama, A. & Katsuyama, T. Histochemistry of the surface mucous gel layer of the human colon. Gut 40, 782–789 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Park, S. Y. et al. Proximal shift in the distribution of adenomatous polyps in Korea over the past ten years. Hepato-gastroenterology 56, 677–681 (2009).

    PubMed  Google Scholar 

  124. Larsen, I. K. & Bray, F. Trends in colorectal cancer incidence in Norway 1962–2006: an interpretation of the temporal patterns by anatomic subsite. Int. J. Cancer 126, 721–732 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Toyoda, Y., Nakayama, T., Ito, Y., Ioka, A. & Tsukuma, H. Trends in colorectal cancer incidence by subsite in Osaka, Japan. Jpn J. Clin. Oncol. 39, 189–191 (2009).

    Article  PubMed  Google Scholar 

  126. Singh, H., Demers, A. A., Xue, L., Turner, D. & Bernstein, C. N. Time trends in colon cancer incidence and distribution and lower gastrointestinal endoscopy utilization in Manitoba. Am. J. Gastroenterol. 103, 1249–1256 (2008).

    Article  PubMed  Google Scholar 

  127. Png, C. W. et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am. J. Gastroenterol. 105, 2420–2428 (2010).

    Article  CAS  PubMed  Google Scholar 

  128. Furne, J., Springfield, J., Koenig, T., DeMaster, E. & Levitt, M. D. Oxidation of hydrogen sulfide and methanediol to thiosulate by rat tissues: a specialized function of the colonic mucosa. Biochem. Pharmacol. 62, 255–259 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010). This article demonstrates that tetrathionate, a metabolic by-product of the microbiota and human tissue combined, serves as an electron acceptor to enhance the physiology of a gut pathogen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in E.C.M.'s laboratory is supported by the US National Institutes of Health (DK084214 and DK034933) and a Global Probiotics Council Young Investigator Grant. N.M.K. is supported by the University of Michigan (Ann Arbor, USA) Elizabeth M. Crosby faculty research grant. E.A.C. is supported by the University of Michigan Genetics Training Grant (GM07544).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric C. Martens.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Eric C. Martens's homepage

CAZy

Glossary

Inflammatory bowel disease

A group of pathologies that are characterized by inflammation in the gut; the most notable examples are Crohn's disease and ulcerative colitis, which involve inflammation in the distal small intestine or the colon. These diseases are thought to stem from a congruence of host susceptibility factors (such as a genetic predisposition to uncontrolled inflammatory responses or reduced mucosal immunity) and stimulation by environmental or microbiological (bacterial and viral) triggers.

Glycans

Polymers of multiple simple sugars connected by covalent linkages. Glycans may be attached to other molecules such as lipids (forming glycolipids) and proteins (forming glycoproteins). Like nucleic acids, glycans have polarity: a linear molecule has one reducing end and one non-reducing end. Here, the term glycan is used synonymously with polysaccharide.

Short-chain fatty acids

Linear and branched fatty acids that contain six or fewer carbon atoms and are produced in addition to lactic and formic acids as end products of bacterial fermentation. These molecules are also referred to as volatile fatty acids. Examples include acetic, propionic and butyric acids.

Mucus

A viscous mixture consisting predominantly of mucin glycoproteins, which may be either attached to cell membranes or secreted from the cell in soluble form. Mucus frequently contains other secreted host compounds, such as secretory immunoglobulin A and antimicrobial peptides.

Glycosidic linkages

Chemical connections that occur between numbered carbon atoms in two sugar monomers, mediated by a shared oxygen atom. These bonds can be in the α- or β-conformation, and multiple linkages may be connected in linear or branched chains to construct more complex glycan structures.

Hemicellulose

A heterogeneous class of glycans that is found associated with cellulose in the matrix of plant cell walls. Unlike highly insoluble cellulose, hemicelluloses have more amorphous and flexible structures that help bind cellulose to pectin fibrils. The type and amount of hemicellulose in the plant cell wall is dependent on the botanical origin and includes molecules such as xylan, xyloglucan, galactomannan and glucomannan.

Pectin

A diverse class of polysaccharides composed of either a homopolymer of α1,4-linked galacturonic acid or a heteropolymer containing galacturonic acid and rhamnose (called rhamnogalacturon I). Each of these core pectin backbones can be extensively substituted with a range of modifications and glycan branches, including methyl and acetyl groups, monosaccharides such as xylose, and longer chains such as β-galactans and α-arabinans.

Prebiotics

Functional food components that selectively enhance the abundance or physiology of a subset of bacteria in the microbiota, with the goal of promoting the beneficial effects of these bacteria. Plant fibres that are resistant to human digestion are among the most common prebiotic therapies.

Germ-free mice

Mice that are raised in the complete absence of microbial colonization, usually following aseptic delivery by caesarian section and by housing the animals in sterile isolators that exclude access of environmental microorganisms. Other animal species such as rats, pigs and chickens have also been reared under germ-free conditions.

Food chains

Arrangements of multiple species in space and time that allow some members to feed either directly on others or on their by-products. Keystone members, which act first in a food chain, are particularly important because their absence also influences the status of the dependent species that are downstream in the food chain.

ABC transporters

(ATP-binding cassette transporters). A protein superfamily that is found in almost every form of life from bacteria to humans. These systems are typically composed of three main components: a solute-binding protein that binds ligands and dictates specificity, a membrane transporter through which the ligand passes, and an ATPase that provides the energy to drive ligand transport. Bacteria use ABC importers to take up nutrients such as iron, peptides or sugars, and ABC efflux transporters to pump toxic compounds out of the cell.

Cellulosome

An extracellular multienzyme complex that is formed in some Gram-positive bacteria and fungi. Cellulosomes bind and degrade plant cell wall polysaccharides that are otherwise resistant to degradation, including cellulose. Scaffoldin, the major non-enzymatic structural component, connects the enzymes via interactions between dockerin domains in the enzymes and cohesin modules in scaffoldin.

Human Microbiome Projects

Several ongoing efforts to sequence the microbial communities that are associated with various human body sites, including the gut. A major component of these projects is to sequence cultured 'reference' organisms. However, because many human-associated microorganisms have not yet been isolated in laboratory culture, a second approach is to directly sequence DNA extracted from microbial community samples (metagenomics).

Koch's postulates

Guidelines that are used to establish causality between a potential microbial pathogen and a disease, as published by Robert Koch in1890. The postulates state that a microorganism that causes a disease should be abundant in animals suffering from that disease, isolated from diseased specimens, able to be introduced into healthy animals to cause disease and able to be re-isolated from newly infected hosts.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koropatkin, N., Cameron, E. & Martens, E. How glycan metabolism shapes the human gut microbiota. Nat Rev Microbiol 10, 323–335 (2012). https://doi.org/10.1038/nrmicro2746

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2746

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research