Letter | Published:

Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice

Nature volume 534, pages 263266 (09 June 2016) | Download Citation

Abstract

Immunoglobulin A (IgA), the major class of antibody secreted by the gut mucosa, is an important contributor to gut barrier function1,2,3. The repertoire of IgA bound to gut bacteria reflects both T-cell-dependent and -independent pathways4,5, plus glycans present on the antibody’s secretory component6. Human gut bacterial taxa targeted by IgA in the setting of barrier dysfunction are capable of producing intestinal pathology when isolated and transferred to gnotobiotic mice7,8. A complex reorientation of gut immunity occurs as infants transition from passively acquired IgA present in breast milk to host-derived IgA9,10,11. How IgA responses co-develop with assembly of the microbiota during this period remains poorly understood. Here, we (1) identify a set of age-discriminatory bacterial taxa whose representations define a program of microbiota assembly and maturation during the first 2 postnatal years that is shared across 40 healthy twin pairs in the USA; (2) describe a pattern of progression of gut mucosal IgA responses to bacterial members of the microbiota that is highly distinctive for family members (twin pairs) during the first several postnatal months then generalizes across pairs in the second year; and (3) assess the effects of zygosity, birth mode, and breast feeding. Age-associated differences in these IgA responses can be recapitulated in young germ-free mice, colonized with faecal microbiota obtained from two twin pairs at 6 and 18 months of age, and fed a sequence of human diets that simulate the transition from milk feeding to complementary foods. Most of these responses were robust to diet, suggesting that ‘intrinsic’ properties of community members play a dominant role in dictating IgA responses. The approach described can be used to define gut mucosal immune development in health and disease states and to help discover ways of repairing or preventing perturbations in this facet of host immunity.

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

Primary accessions

European Nucleotide Archive

References

  1. 1.

    et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004)

  2. 2.

    et al. Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice. J. Exp. Med. 190, 915–922 (1999)

  3. 3.

    , , & IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2, 328–339 (2007)

  4. 4.

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

  5. 5.

    et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000)

  6. 6.

    & N-Glycans on secretory component: mediators of the interaction between secretory IgA and Gram-positive commensals sustaining intestinal homeostasis. Gut Microbes 2, 287–293 (2011)

  7. 7.

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

  8. 8.

    et al. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Sci. Transl. Med. 7, 276r24 (2015)

  9. 9.

    The mucosal immune system and its integration with the mammary glands. J. Pediatr. 156 (Suppl.), S8–S15 (2010)

  10. 10.

    et al. Limited expression of APRIL and its receptors prior to intestinal IgA plasma cell development during human infancy. Mucosal Immunol. 7, 467–477 (2014)

  11. 11.

    et al. IgA response in preterm neonates shows little evidence of antigen-driven selection. J. Immunol. 189, 5449–5456 (2012)

  12. 12.

    et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510, 417–421 (2014)

  13. 13.

    et al. Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science 351, aad3311 (2016)

  14. 14.

    et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014)

  15. 15.

    et al. Pan-genome of the dominant human gut-associated archaeon, Methanobrevibacter smithii, studied in twins. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4599–4606 (2011)

  16. 16.

    et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010)

  17. 17.

    & The marriage of nutrigenomics with the microbiome: the case of infant-associated bifidobacteria and milk. Am. J. Clin. Nutr. 99, 697S–703S (2014)

  18. 18.

    & Species assemblages and indicator species: the need for a flexible asymmetrical approach. Ecol. Monogr. 67, 345–366 (1999)

  19. 19.

    et al. Food consumption patterns of infants and toddlers: where are we now? J. Am. Diet. Assoc. 110 (Suppl.), S38–S51 (2010)

  20. 20.

    , , & Secretory IgA is concentrated in the outer layer of the colonic mucus along with gut bacteria. Pathogens 3, 390–403 (2014)

  21. 21.

    , & Stress at the intestinal surface: catecholamines and mucosa-bacteria interactions. Cell Tissue Res. 343, 23–32 (2011)

  22. 22.

    et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015)

  23. 23.

    & Exploring the role of environmental enteropathy in malnutrition, infant development and oral vaccine response. Phil. Trans. R. Soc. B 370, 20140143 (2015)

  24. 24.

    , , , & Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl. Med. 6, 220ra11 (2014)

  25. 25.

    et al. Subsampled open-reference clustering creates consistent, comprehensive OTU definitions and scales to billions of sequences. PeerJ 2, e545 (2014)

  26. 26.

    et al. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4516–4522 (2011)

  27. 27.

    & Classification and regression by randomForest. R News 2 (3), 18–22 (2002)

  28. 28.

    & Associations between species and groups of sites: indices and statistical inference. Ecology 90, 3566–3574 (2009)

  29. 29.

    et al. vegan: Community Ecology Package. (2014)

  30. 30.

    , & lmerTest: tests for random and fixed effects for linear mixed effect models (lmer objects of lme4 package). (2013)

Download references

Acknowledgements

We thank D. O’Donnell, M. Karlsson, J. Serugo, and S. Wagoner for help with gnotobiotic husbandry; S. Deng, J. Guruge, J. Hoisington-Lopez and M. Meier for technical assistance; G. Dantas for help with maintaining our archive of de-identified human samples; and N. Griffin for comments about facets of the data analysis. This work was supported by grants from the National Institutes of Health (DK30292, DK052574), the Children’s Discovery Institute, the Bill & Melinda Gates Foundation, and the Crohn’s and Colitis Foundation of America. J.D.P. is a member of the Washington University Medical Scientist Training Program (National Institutes of Health GM007200).

Author information

Affiliations

  1. Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Joseph D. Planer
    • , Yangqing Peng
    • , Andrew L. Kau
    • , Laura V. Blanton
    •  & Jeffrey I. Gordon
  2. Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Joseph D. Planer
    • , Yangqing Peng
    • , Andrew L. Kau
    • , Laura V. Blanton
    •  & Jeffrey I. Gordon
  3. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • I. Malick Ndao
    • , Phillip I. Tarr
    •  & Barbara B. Warner

Authors

  1. Search for Joseph D. Planer in:

  2. Search for Yangqing Peng in:

  3. Search for Andrew L. Kau in:

  4. Search for Laura V. Blanton in:

  5. Search for I. Malick Ndao in:

  6. Search for Phillip I. Tarr in:

  7. Search for Barbara B. Warner in:

  8. Search for Jeffrey I. Gordon in:

Contributions

B.B.W., P.I.T., M.I. and G.D. designed, enrolled and collected specimens from participants in the twin study. J.D.P. performed BugFACS and 16S rRNA analyses on human faecal samples. J.D.P. and J.I.G. designed the gnotobiotic mouse experiments; J.D.P. and Y.P. performed these experiments. J.D.P., A.L.K., L.V.B., Y.P., and J.I.G. analysed the data. J.D.P. and J.I.G. wrote the paper.

Competing interests

J.I.G. is co-founder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health. The other authors declare that they have no competing interests.

Corresponding author

Correspondence to Jeffrey I. Gordon.

16S rRNA sequences in raw format before post-processing and data analysis have been deposited at the European Nucleotide Archive under project PRJEB11697.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Tables

    This file contains Supplementary Tables 1-22.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature17940

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.