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.

  • Article
  • Published:

Bacterial and host fucosylation maintain IgA homeostasis to limit intestinal inflammation in mice

Nature Microbiology volume 10, pages 126–143 (2025) Cite this article

Subjects

Abstract

Inflammatory bowel disease is associated with several genetic risk loci. Loss-of-function mutation in the α1,2-fucosyltransferase (fut2) gene, which alters fucosylation on the surface of intestinal epithelial cells, is one example. However, whether bacterial fucosylation can contribute to gut inflammation is unclear. Here we show that host fucosylation status influences fucosylation biosynthesis by gut commensal bacteria. Mice colonized with faecal microbiota of Fut2 knockout mice or Bacteroides fragilis with lower surface fucosylation are predisposed to colitis. This was supported by human cohort data showing that bacterial fucosylation levels decrease in patients with inflammatory bowel disease and correlate with intestinal inflammation. Using a mouse model for Bacteroides fragilis to explore the role of fucosylation in gut immunity, we show that the fucosylation status of epithelial cells and bacteria is critical for maintaining B cell responses in the gut. Host-derived and dietary fucose mediate immunoglobulin A (IgA) recognition of gut microbiota, and this interaction facilitates the translocation of commensals to Peyer’s patches and alters the immune landscape of Peyer’s patches with increased germinal centre B cells and IgA-secreting antigen-specific B cells. Finally, dietary fucose enhances the IgA response against Salmonella and protects against systemic bacterial dissemination. This highlights the role of host and bacterial fucosylation in maintaining IgA homeostasis and immune escape mechanisms.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Host fucosylation modulates gut bacterial fucosylation at both DNA and mRNA levels.
The alternative text for this image may have been generated using AI.
Fig. 2: Loss of bacterial fucosylation promotes intestinal inflammation and increases colitis risk.
The alternative text for this image may have been generated using AI.
Fig. 3: Gut bacterial fucosylation drives activation of GC B cells and induces specific IgA production in PPs.
The alternative text for this image may have been generated using AI.
Fig. 4: Bacterial fucosylation mediates IgA binding to gut bacteria.
The alternative text for this image may have been generated using AI.
Fig. 5: IgA coating facilitates bacterial entry into PPs, activating GC B cells and inducing bacteria-specific PCs.
The alternative text for this image may have been generated using AI.
Fig. 6: l-Fucose rescues B cell development in PPs of Fut2−/− mice and protects mice from Salmonella infection.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

Data availability

Metagenomic sequencing and metatranscriptomic sequencing data were deposited in the NIH SRA database under accession number PRJNA1060661. The remaining data are available within the article, Supplementary Information or source data files. Source data are provided with this paper.

References

  1. Schaffer, C. & Messner, P. Emerging facets of prokaryotic glycosylation. FEMS Microbiol. Rev. 41, 49–91 (2017).

    Article  PubMed  Google Scholar 

  2. Goto, Y., Uematsu, S. & Kiyono, H. Epithelial glycosylation in gut homeostasis and inflammation. Nat. Immunol. 17, 1244–1251 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Brazil, J. C. & Parkos, C. A. Finding the sweet spot: glycosylation mediated regulation of intestinal inflammation. Mucosal. Immunol. 15, 211–222 (2022).

    Article  CAS  PubMed  Google Scholar 

  4. McGovern, D. P. B. et al. Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum. Mol. Genet. 19, 3468–3476 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Parmar, A. S. et al. Association study of FUT2 (rs601338) with celiac disease and inflammatory bowel disease in the Finnish population. Tissue Antigens 80, 488–493 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Weiss, G. A., Chassard, C. & Hennet, T. Selective proliferation of intestinal Barnesiella under fucosyllactose supplementation in mice. Br. J. Nutr. 111, 1602–1610 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Pickard, J. M. & Chervonsky, A. V. Intestinal fucose as a mediator of host-microbe symbiosis. J. Immunol. 194, 5588–5593 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Kashyap, P. C. et al. Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota. Proc. Natl Acad. Sci. USA 110, 17059–17064 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schluter, J. & Foster, K. R. The evolution of mutualism in gut microbiota via host epithelial selection. PLoS Biol. 10, e1001424 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lei, C. et al. Enteric VIP-producing neurons maintain gut microbiota homeostasis through regulating epithelium fucosylation. Cell Host Microbe 30, 1417–1434.e8 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Coyne, M. J., Reinap, B., Lee, M. M. & Comstock, L. E. Human symbionts use a host-like pathway for surface fucosylation. Science 307, 1778–1781 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Bergman, M., Del Prete, G., van Kooyk, Y. & Appelmelk, B. Helicobacter pylori phase variation, immune modulation and gastric autoimmunity. Nat. Rev. Microbiol. 4, 151–159 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Fletcher, C. M., Coyne, M. J. & Comstock, L. E. Theoretical and experimental characterization of the scope of protein O-glycosylation in Bacteroides fragilis. J. Biol. Chem. 286, 3219–3226 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Fletcher, C. M., Coyne, M. J., Villa, O. F., Chatzidaki-Livanis, M. & Comstock, L. E. A general O-glycosylation system important to the physiology of a major human intestinal symbiont. Cell 137, 321–331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. de Jong, H., Wosten, M. & Wennekes, T. Sweet impersonators: molecular mimicry of host glycans by bacteria. Glycobiology 32, 11–22 (2022).

    Article  PubMed  Google Scholar 

  17. Bunker, J. J. & Bendelac, A. IgA responses to microbiota. Immunity 49, 211–224 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huus, K. E., Petersen, C. & Finlay, B. B. Diversity and dynamism of IgA–microbiota interactions. Nat. Rev. Immunol. 21, 514–525 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Petersen, C. et al. T cell-mediated regulation of the microbiota protects against obesity. Science 365, 340 (2019).

    Article  Google Scholar 

  21. Luck, H. et al. Gut-associated IgA+ immune cells regulate obesity-related insulin resistance. Nat. Commun. 10, 3650 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Huus, K. E. et al. Commensal bacteria modulate immunoglobulin A binding in response to host nutrition. Cell Host Microbe 27, 909–921 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Di Luccia, B. et al. Combined prebiotic and microbial intervention improves oral cholera vaccination responses in a mouse model of childhood undernutrition. Cell Host Microbe 27, 899–908.e5 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Reboldi, A. et al. IgA production requires B cell interaction with subepithelial dendritic cells in Peyer’s patches. Science 352, aaf4822 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Belkaid, Y. & Naik, S. Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol. 14, 646–653 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Cheng, S. J. et al. Altered gut microbiome in FUT2 loss-of-function mutants in support of personalized medicine for inflammatory bowel diseases. FASEB J. 35, 771–780 (2021).

    Article  Google Scholar 

  29. Tang, X. et al. Gut microbiota-mediated lysophosphatidylcholine generation promotes colitis in intestinal epithelium-specific Fut2 deficiency. J. Biomed. Sci. 28, 20 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Romano, P. R. et al. Development of Aleuria aurantia recombinant lectins with altered binding specificities to fucosylated glycans. Biochem. Biophys. Res. Commun. 414, 84–89 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, T. W. et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77, e108–e110 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Henrick, B. M. et al. Bifidobacteria-mediated immune system imprinting early in life. Cell 184, 3884–3898.e11 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Vatanen, T. et al. A distinct clade of Bifidobacterium longum in the gut of Bangladeshi children thrives during weaning. Cell 185, 4280–4297.e12 (2022).

    Article  CAS  PubMed  Google Scholar 

  34. Joglekar, P. et al. Intestinal IgA regulates expression of a fructan polysaccharide utilization locus in colonizing gut commensal. mBio 10, e02324-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nakajima, A. et al. IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria. J. Exp. Med. 215, 2019–2034 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Peterson, D. A., McNulty, N. P., Guruge, J. L. & Gordon, J. I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2, 328–339 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Day, C. J. et al. Glycan:glycan interactions: high affinity biomolecular interactions that can mediate binding of pathogenic bacteria to host cells. Proc. Natl Acad. Sci. USA 112, E7266–E7275 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. de Lau, W. et al. Peyer’s patch M cells derived from Lgr5+ stem cells require SpiB and are induced by RankL in cultured “miniguts”. Mol. Cell. Biol. 32, 3639–3647 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Nagashima, K. et al. Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota. Nat. Immunol. 18, 675–682 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Knoop, K. A. et al. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. J. Immunol. 183, 5738–5747 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Caballero-Flores, G. et al. Maternal immunization confers protection to the offspring against an attaching and effacing pathogen through delivery of IgG in breast milk. Cell Host Microbe 25, 313–323.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Goto, Y. et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345, 1254009 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498–502 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Theodoratou, E. et al. The role of glycosylation in IBD. Nat. Rev. Gastroenterol. Hepat. 11, 588–600 (2014).

    Article  CAS  Google Scholar 

  45. Hooper, L. V., Xu, J., Falk, P. G., Midtvedt, T. & Gordon, J. I. A molecular sensor that allows a gut commensal to control its nutrient foundation in a competitive ecosystem. Proc. Natl Acad. Sci. USA 96, 9833–9838 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Kawamoto, S. et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336, 485–489 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Mirpuri, J. et al. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes 5, 28–39 (2014).

    Article  PubMed  Google Scholar 

  49. Alipour, M. et al. Mucosal barrier depletion and loss of bacterial diversity are primary abnormalities in paediatric ulcerative colitis. J. Crohns Colitis 10, 462–471 (2016).

    Article  PubMed  Google Scholar 

  50. Rengarajan, S. et al. Dynamic immunoglobulin responses to gut bacteria during inflammatory bowel disease. Gut Microbes 11, 405–420 (2020).

    Article  PubMed  Google Scholar 

  51. Kau, A. L. et al. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Sci. Transl. Med. 7, 276ra24 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen, H. et al. BCR selection and affinity maturation in Peyer’s patch germinal centres. Nature 582, 421–425 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sterlin, D. et al. Human IgA binds a diverse array of commensal bacteria. J. Exp. Med. 217, e20181635 (2020).

    Article  PubMed  Google Scholar 

  54. Mathias, A. & Corthésy, B. Recognition of Gram-positive intestinal bacteria by hybridoma- and colostrum-derived secretory immunoglobulin A is mediated by carbohydrates. J. Biol. Chem. 286, 17239–17247 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. van de Bovenkamp, F. S. et al. Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc. Natl Acad. Sci. USA 115, 1901–1906 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Raju, T. S. Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr. Opin. Immunol. 20, 471–478 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. Immunity 43, 541–553 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Owen, R. L. & Jones, A. L. Epithelial cell specialization within human Peyer’s patches: an ultrastructural study of intestinal lymphoid follicles. Gastroenterology 66, 189–203 (1974).

    Article  CAS  PubMed  Google Scholar 

  59. Hase, K. et al. Uptake through glycoprotein 2 of FimH bacteria by M cells initiates mucosal immune response. Nature 462, 226–U101 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Mabbott, N. A., Donaldson, D. S., Ohno, H., Williams, I. R. & Mahajan, A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 6, 666–677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rogier, E. W. et al. Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. Proc. Natl Acad. Sci. USA 111, 3074–3079 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Harriman, G. R. et al. Targeted deletion of the IgA constant region in mice leads to IgA deficiency with alterations in expression of other Ig isotypes. J. Immunol. 162, 2521–2529 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Garcia-Bayona, L. & Comstock, L. E. Streamlined genetic manipulation of diverse Bacteroides and Parabacteroides isolates from the human gut microbiota. mBio 10, e01762–19 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gu, X. et al. Neutral ceramidase mediates nonalcoholic steatohepatitis by regulating monounsaturated fatty acids and gut IgA+ B cells. Hepatology 73, 901–919 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L.E. Comstock for providing B. fragilis NCTC9343 with the ΔGMD, ΔFKP, ΔGMD−FCLΔFKP strains, and the use of anaerobic chambers and the GF facility in the Functional Microbiomics Core at the University of Louisville. This study was supported by grants from the National Institutes of Health (NIH): R21AI159194, R01DK131442, R01DK115406 and R01AA030756 (Z.D.). Y.T. is supported by NIH R01HL160927. Research reported in this publication was partially supported by the National Institute of General Medical Sciences of the NIH under Award Number P20GM113226 (C.J.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank J. Ainsworth for editorial assistance.

Author information

Author notes

  1. These authors contributed equally: Chao Lei, Chao Luo.

Authors and Affiliations

  1. Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, KY, USA

    Chao Lei, Zhishan Xu, Mukesh K. Sriwastva, Ting Wang & Zhongbin Deng

  2. Brown Cancer Center, University of Louisville, Louisville, KY, USA

    Chao Lei, Zhishan Xu, Mukesh K. Sriwastva, Ting Wang & Zhongbin Deng

  3. Department of Central Laboratory, the Affiliated Huaian No. 1 People’s Hospital, Nanjing Medical University, Huaian, China

    Chao Luo, Shu Ding & Qilong Wang

  4. Digestive Disease Center, the Affiliated Huaian No. 1 People’s Hospital, Nanjing Medical University, Huaian, China

    Chao Luo, Qilong Wang & Xiaozhong Yang

  5. Department of Medicine, University of Louisville, Louisville, KY, USA

    Gerald Dryden, Manman Xu & Craig J. McClain

  6. Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA

    Yi Tan

  7. Alcohol Research Center, University of Louisville, Louisville, KY, USA

    Craig J. McClain & Zhongbin Deng

  8. Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA

    Craig J. McClain & Zhongbin Deng

  9. Robley Rex VA Medical Center, Louisville, KY, USA

    Craig J. McClain

Authors
  1. Chao Lei
    View author publications

    Search author on:PubMed Google Scholar

  2. Chao Luo
    View author publications

    Search author on:PubMed Google Scholar

  3. Zhishan Xu
    View author publications

    Search author on:PubMed Google Scholar

  4. Shu Ding
    View author publications

    Search author on:PubMed Google Scholar

  5. Mukesh K. Sriwastva
    View author publications

    Search author on:PubMed Google Scholar

  6. Gerald Dryden
    View author publications

    Search author on:PubMed Google Scholar

  7. Ting Wang
    View author publications

    Search author on:PubMed Google Scholar

  8. Manman Xu
    View author publications

    Search author on:PubMed Google Scholar

  9. Yi Tan
    View author publications

    Search author on:PubMed Google Scholar

  10. Qilong Wang
    View author publications

    Search author on:PubMed Google Scholar

  11. Xiaozhong Yang
    View author publications

    Search author on:PubMed Google Scholar

  12. Craig J. McClain
    View author publications

    Search author on:PubMed Google Scholar

  13. Zhongbin Deng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

C. Lei and Z.D. designed the study, analysed and interpreted the data, and prepared the paper. C. Lei, Z.X., M.K.S. and T.W. performed the experiments and interpreted the data. C. Luo and S.D. collected and analysed the data for human samples. M.X. helped in the bioinformatics analysis. G.D., Y.T., Q.W., X.Y. and C.J.M. interpreted the findings.

Corresponding authors

Correspondence to Chao Lei or Zhongbin Deng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Microbiology thanks Andrea Cerutti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Microbiota_Composition.

Impact of Host Fucosylation on Gut microbiota Composition and Functions in mice. (a-c) DSS (2.5%) induced colitis model in WT and Fut2-/- mice with gut microbiota depletion using antibiotic cocktail treatment for 2 weeks. Weight loss (a), colon lengths (b), and representative (H&E) staining of colon tissue, with a scale bar of 100 µm (c) in animals following the induction of colitis. (d) Rarefaction curve depicting the Chao1 and Shannon indices of the gut bacteriome. (e) Rarefaction curve illustrating the Chao1 and Shannon indices of the gut archaeome. (f-g) Principal coordinate analysis (PCoA) of the gut bacteriome (f) and archaeome (g). (h) Percentage distribution of bacteria and archaea in the gut microbiota. (i-j) Heatmap illustrating gut microbiota composition at the phylum level (i) and at the species level (j) in WT and Fut2-/- mice. (k-l) Cladogram (k) and linear discriminant analysis (LDA) effect size (LEfSe) (l) analysis of gut microbiota. Error bars represent mean ± SEM. ns, not significant. Statistical comparisons were performed using two-tailed unpaired Student’s t test (a, b, h). Heatmap data were normalized using Z-score. n = 3 (a-c) independent biological samples.

Source data

Extended Data Fig. 2 Bacterial Fucosylation.

Host Fucosylation Modulates Gut Bacterial Fucosylation. (a) Heatmap illustrating gut microbiota composition in genus level. (b) Heatmap displaying enriched Gene Ontology (GO) terms in the gut microbiota of WT and Fut2-/- mice. Heatmap data were normalized using Z-score (a,b). (c) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of WT and Fut2-/- mice. (d-e) Statistical Analysis of Metagenomic (d, n = 6) and Metatranscriptomic Profiles plot, (e, n = 4) of carbohydrate-active enzymes from the CAZy database in the gut microbiota of WT and Fut2-/- mice.

Source data

Extended Data Fig. 3 Bacterial Fucosylation_1.

Fucose Modulates Gut Bacterial Fucosylation. (a-b) GO enrichment analysis of genes involved in bacterial fucose metabolism at the DNA (a) and mRNA level (b). Heatmap data were normalized using Z-score. (c) Representative plots of flow cytometry and the percentage of AAL+ positive bacteria cultured in TYG broth with indicated carbon sources: glucose and fucose. Error bars represent mean ± SEM. ns, not significant. Statistical comparisons were performed using two-tailed unpaired Student’s t test. n = 3 independent biological samples.

Source data

Extended Data Fig. 4 Intestinal Inflammation.

Loss of Bacterial Fucosylation Promotes Intestinal Inflammation and Increases Colitis Risk. (a) Representative plots of flow cytometry and the percentage of AAL positive gut bacteria in GF mice transplanted with fecal microbiota of WT mice (FMT-WT) and Fut2-/- mice (FMT-Fut2-/-). (b-f) Female, 6-week-old, antibiotic-pretreated C57BL/6 J mice were colonized with BFWT9343 or BFΔΔ9343 strains for 2 weeks. BFWT9343 (blue) and BFΔΔ9343 (pink) colony-forming units (CFU) in fecal pellets (b) were determined daily for 6 days. Body weight changes (c), representative images of the cecum (d), and representative H&E staining of the cecum (e) and colon (f). Scale bar: 100 µm. (g) TIMER2.0 analysis of correlation between fut2 and B cell subtypes in the intestine. COAD database (n = 458) and xCell algorithm was used for the Spearman correlation analysis. The data are representative of three (a, e, f) independent experiments. Error bars represent mean ± SEM. Statistical comparisons were performed using two-tailed unpaired Student’s t test (a-c). n = 5 (a, b-f) independent biological samples. The scale bar represents 100 µm.

Extended Data Fig. 5 GC B Cells.

Gut Bacterial Fucosylation Modulates Activation of GC B Cells and Induction of Specific IgA Production in PPs. (a) Representative plots of flow cytometry and the frequency of follicular T cells (n = 6), regulatory B cells (n = 5) and dendritic cells (n = 4) in PPs of WT and Fut2-/- mice. Independent biological samples. (b) FISH analysis of microbiota localization in the colon using a universal bacterial 16S rRNA gene probe (Red). (c) Representative distal colons of WT (Top) and Fut2-/- (Bottom) mice stained with PAS-AB. (d) Representative plots of flow cytometry and the frequency of activated B220+ GL-7+IgD− GC B cells in PPs of WT and Fut2-/- mice at the age of 3-4 weeks and 20-24 weeks. (e) Representative plots of flow cytometry and the frequency of activated B220+ GL-7+IgD− GC B cells and CD138+IgA+ PCs in PPs of WT and Fut2-/- mice with antibiotic treatment for depletion of gut microbiota. (f-g) Representative ELISPOT and quantification of B. fragilis 9343-specific IgA secreting plasma cells and total IgA secreting plasma cells in PPs (f) and small intestinal (SI) LP (g) of GF mice that were colonized with B. fragilis WT9343 strain or ΔΔ9343 strain for 14 days. (h) ELISA quantification of B. fragilis 9343-specific IgA in fecal samples of GF mice that were colonized with B. fragilis WT9343 strain or ΔΔ9343 strain for 14 days. Error bars represent mean ± SEM. ns, not significant. Statistical comparisons were performed using two-tailed unpaired Student’s t test (a, e, h), two-way ANOVA with Sidak’s multiple comparisons test (d, f, g). n = 3 (d), n = 5 (e-h) independent biological samples.

Source data

Extended Data Fig. 6 IgA Binding to Gut Bacteria.

Bacterial Fucosylation Mediates IgA Binding to Gut Bacteria. (a) Schematic representation of the fucosyltransferases, GMD, FKP and capsular polysaccharide cassettes distribution in genome of B. fragilis 9343. (b-c) Representative plots of flow cytometry (b) and the percentage (c) of AAL binding and IgA binding to B. fragilis strains with a single deletion of fucosyltransferase in the genome. (d) Representative plots of flow cytometry and the percentage of gut bacteria binding with intestinal IgA extracted from conventional WT C57BL6 mice. Gut bacteria were isolated from Rag1-/- mice and pretreated with or without AAL before coating with IgA. (e) Representative flow cytometry and the percentage of BFWT9343 or BFΔΔ9343 strains binding with intestinal IgA. WT9343 or ΔΔ9343 were recovered from B. fragilis gnotobiotic mice. (f) Relative expression of genes encoding fucosylation biosynthesis in BFΔΔ9343 with or without IgA coating, assessed by qRT-PCR with the housekeeping gene gyrB as an internal reference. The data are representative of two independent experiments (b, d, e). Error bars represent mean ± SEM. ns, not significant. Statistical comparisons were performed using One-way ANOVA with Tukey’s multiple comparisons test (c); two-tailed unpaired Student’s t test (d, e, f). n = 3 (c, d, f), n = 5 (e) independent biological samples.

Source data

Extended Data Fig. 7 Fucosylaton of GP2.

Fucosylaton of GP2 mediates the interaction of IgA in in the follicle-associated epithelium (FAE) of PPs. (a) Co-immunoprecipitation (co-IP) of IgA and GP2. Immunocomplexes were co-IP from small intestine IEC lysate of WT mice or Fut2-/- mice with anti-GP2 antibody and then were stained for immunoblotting of IgA by anti-IgA antibody. Insert digital: Mean Density. (b) Cross-section immunostaining of GP2 (green) and UEA-1 (red) in the follicle-associated epithelium (FAE) of PPs. Scale bars, 50 μm. (c) Cross-section immunostaining of GP2 (green), IgA (purple) and UEA-1 (red) in the follicle-associated epithelium (FAE) of PPs of WT mice or Fut2-/- mice. Scale bars, 50 μm. (d) Co-IP of IgA and GP2. IgA-/- ileal lysate was incubated with biotinylated anti-mouse GP2 antibody and captured using streptavidin agarose beads. For fucosidase O treatment groups, beads capturing GP2 were incubated with 10 U of fucosidase O at 37°C for 6 hours prior to IgA pulldown. The beads were washed and subsequently incubated with WT ileal lysate to allow IgA binding. Bound proteins were eluted and analyzed by Western blotting using anti-IgA-HRP antibody. The data are representative of two independent experiments (a-d).

Source data

Extended Data Fig. 8 Early life IgA Coating Bacteria.

Early life IgA Coating Bacteria Facilitates the Activation of GC B Cells in PPs. (a) The number of GL-7+IgD− GC B cells in PPs of IgA-/- mice after antibiotic treatment. (b) Representative plots of flow cytometry and the frequency of activated B220+ GL-7+IgD− GC B cells in PPs of WT and IgA-/- mice at the age of 3-4 weeks and 20-24 weeks. (c) Representative plots of flow cytometry and the frequency of activated B220+ GL-7+IgD− GC B cells in PPs of WT and IgA-/- mice. 5-month-old IgA-/- mice were fed with WT microbiota in drinking water for 3 weeks. (d-e) Representative flow cytometry and the frequency of GL-7+IgD− GC B cells (B) and CD138+IgA+ B cells (C) in PPs of WT and pIgR-/- mice. pIgR-/- mice were treated with antibiotics and colonized with BFWT9343 or BFΔΔ9343 for 2 weeks. The data are representative of two independent experiments (a, d, e). Error bars represent mean ± SEM. ns, not significant. Statistical comparisons were performed using two-tailed unpaired Student’s t test (a, c, d, e); two-way ANOVA with Sidak’s multiple comparisons test (b). n = 3 (c), n = 4 (b), n = 5 (a, d, e) independent biological samples.

Source data

Extended Data Fig. 9 L-fucose increase IgA coating.

L-fucose increase BFΔGMD9343 surface fucosylation and IgA coating in the faeces of gnotobiotic mice. (a) Representative plots of flow cytometry and the frequency of B220+GL-7+IgD− GC B cells and CD138+IgA+ B cells in PPs of WT littermate controls and IgA-/- mice fed with or without 2.5% L-fucose in drinking water for 2 weeks. (b) Representative plots of flow cytometry of AAL+ and IgA+ bacteria in fecal samples of BFΔGMD9343 mono-colonized GF mice with or without L-fucose in drinking water. GF mice were colonized with BFΔGMD9343 for 1 week, followed by 2.5% L-fucose in drinking water or untreated water for 2 weeks. (c-e) L-fucose enhances the specific IgA response to cholera toxin (CT) in C57BL/6 mice. (c) Schematic representation illustrating CT vaccination with or without 2.5% L-fucose in the drinking water. (d) Determination of CT-specific IgA in the small intestinal and colonic lumen using ELISA. (e) Enumeration of CT-specific ASC in PPs assessed using an ELISPOT. (f-g) Fucosylated B. fragilis NCTC9343 increases the specific IgA response to CT in gnotobiotic mice. (f) Schematic illustration depicting CT vaccination in gnotobiotic mice using BFWT9343 or BFΔΔ9343 strains. (g) Quantification of CT-specific ASC in PPs determined using an ELISPOT. The data are representative of two independent experiments (d, e). Error bars represent mean ± SEM. ns, not significant. Statistical comparisons were performed using two-tailed unpaired Student’s t test (d, e, g); two-way ANOVA with Sidak’s multiple comparisons test (a). n = 3 (a), n = 4 (g), n = 5 (d, e) independent biological samples.

Source data

Extended Data Fig. 10 Salmonella Infection.

L-Fucose Feeding Protects Mice from Salmonella Infection. Salmonella infection in WT littermate controls and IgA-/- mice with or without L-fucose pre-treatment. (a) Salmonella load in feces, MLN, spleen and cecum tissue 72 hours after infection. (b) Representative (H&E) staining of cecum tissue, with a scale bar of 100 µm. Error bars represent mean ± SEM. ns, not significant. Statistical comparisons were performed using two-way ANOVA with Sidak’s multiple comparisons test (a). n = 3 independent biological samples.

Source data

Supplementary information

Source data

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lei, C., Luo, C., Xu, Z. et al. Bacterial and host fucosylation maintain IgA homeostasis to limit intestinal inflammation in mice. Nat Microbiol 10, 126–143 (2025). https://doi.org/10.1038/s41564-024-01873-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41564-024-01873-w

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing