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Complex N-glycan breakdown by gut Bacteroides involves an extensive enzymatic apparatus encoded by multiple co-regulated genetic loci

Nature Microbiology volume 4, pages 1571–1581 (2019)Cite this article

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Abstract

Glycans are the major carbon sources available to the human colonic microbiota. Numerous N-glycosylated proteins are found in the human gut, from both dietary and host sources, including immunoglobulins such as IgA that are secreted into the intestine at high levels. Here, we show that many mutualistic gut Bacteroides spp. have the capacity to utilize complex N-glycans (CNGs) as nutrients, including those from immunoglobulins. Detailed mechanistic studies using transcriptomic, biochemical, structural and genetic techniques reveal the pathway employed by Bacteroides thetaiotaomicron (Bt) for CNG degradation. The breakdown process involves an extensive enzymatic apparatus encoded by multiple non-adjacent loci and comprises 19 different carbohydrate-active enzymes from different families, including a CNG-specific endo-glycosidase activity. Furthermore, CNG degradation involves the activity of carbohydrate-active enzymes that have previously been implicated in the degradation of other classes of glycan. This complex and diverse apparatus provides Bt with the capacity to access the myriad different structural variants of CNGs likely to be found in the intestinal niche.

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Fig. 1: Complex N-glycans as a nutrient source for Bacteroides species.
Fig. 2: Genes upregulated in Bt during growth on CNG.
Fig. 3: The degradation of bi-antennary CNG by recombinant enzymes from Bt.
Fig. 4: Activity of BT1044GH18 endo β-GlcNAcase on immunoglobulin substrates and structure of the enzyme.
Fig. 5: GH20 β-hexosaminidase activity against α1AGp.
Fig. 6: Crystal structure of BT0459GH20

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Data availability

The full RNA-Seq data are provided in Supplementary Table 1 and have also been submitted to https://www.ncbi.nlm.nih.gov/geo/ with the accession number GSE129572. The crystal structures are deposited in the Protein Data Bank under the accession numbers 6Q63 and 6Q64. The other data that support the findings in this paper are available upon request from the corresponding authors.

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Acknowledgements

We thank C. Morland (Newcastle University, UK) for his expert technical assistance, and F. Cuskin (Newcastle University, UK) and L. Royle (Ludger, UK) for insightful conversations about the data. We would like to thank Diamond Light Source (Oxfordshire, UK) for beamtime (proposal mx13587 and mx18598) and the staff of beamline I03 and 104-1 for assistance with crystal testing and data collection. We thank J. Casement (Bioinformatics Support Unit, Newcastle University, UK) for analysing the raw RNA-Seq data. We thank J. Sonnenberg (Stanford, USA) for the ΔBT0455 Bt strain, R. Lewis (Newcastle University, UK) for his guidance and advice in looking for structural homologues and R. Hirt (Newcastle University, UK) for his advice on phylogenetics. The work was funded by the BBSRC/Innovate UK IB catalyst award to D.N.B. ‘Glycoenzymes for Bioindustries’ (BB/M029018/1).

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  1. These authors contributed equally: Justina Briliūtė, Paulina A. Urbanowicz.

Authors and Affiliations

  1. Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK

    Justina Briliūtė, Arnaud Baslé, Didier A. Ndeh, Elisabeth C. Lowe, David N. Bolam & Lucy I. Crouch

  2. Ludger Ltd, Culham Science Centre, Abingdon, UK

    Paulina A. Urbanowicz, Osmond Rebello, Jenifer Hendel & Daniel I. R. Spencer

  3. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA

    Ana S. Luis & Eric C. Martens

  4. Diamond Light Source, Didcot, UK

    Neil Paterson

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Contributions

J.B., A.S.L. and L.I.C. carried out enzyme kinetics. J.B., P.A.U., A.S.L., O.R. and L.I.C. carried out enzymes assays. J.H. made substrates. J.B. and L.I.C. carried out Bacteroides growth. L.I.C. carried out the whole-cell assays. P.A.U. and O.R. carried out the LC–MS. P.A.U. and L.I.C. analysed the LC–MS data. J.B. and L.I.C. purified proteins and set up crystal trays. A.B. collected crystals and data. A.B. and N.P. solved crystal structures. J.B., D.N. and L.I.C. produced Bacteroides gene deletion strains. L.I.C. carried out the bioinformatic analysis. L.I.C., D.N.B., P.A.U., J.B., A.S.L., D.I.R.S. and E.C.M. designed experiments. L.I.C., E.C.L. and D.N.B wrote the manuscript.

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Correspondence to David N. Bolam or Lucy I. Crouch.

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Supplementary Information

Supplementary Results and Discussion, legends for Supplementary Tables 1–13, Supplementary Figures 1–24, and Supplementary References.

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Supplementary Data 1

RNA seq data table showing average normalized base counts in glucose and bovine α1-acid glycoprotein (α1AGP) samples.

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Briliūtė, J., Urbanowicz, P.A., Luis, A.S. et al. Complex N-glycan breakdown by gut Bacteroides involves an extensive enzymatic apparatus encoded by multiple co-regulated genetic loci. Nat Microbiol 4, 1571–1581 (2019). https://doi.org/10.1038/s41564-019-0466-x

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