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Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation

Nature volume 521, pages 9093 (07 May 2015) | Download Citation


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The proliferation of genetically modified mouse models has exposed phenotypic variation between investigators and institutions that has been challenging to control1,2,3,4,5. In many cases, the microbiota is the presumed cause of the variation. Current solutions to account for phenotypic variability include littermate and maternal controls or defined microbial consortia in gnotobiotic mice6,7. In conventionally raised mice, the microbiome is transmitted from the dam2,8,9. Here we show that microbially driven dichotomous faecal immunoglobulin-A (IgA) levels in wild-type mice within the same facility mimic the effects of chromosomal mutations. We observe in multiple facilities that vertically transmissible bacteria in IgA-low mice dominantly lower faecal IgA levels in IgA-high mice after co-housing or faecal transplantation. In response to injury, IgA-low mice show increased damage that is transferable by faecal transplantation and driven by faecal IgA differences. We find that bacteria from IgA-low mice degrade the secretory component of secretory IgA as well as IgA itself. These data indicate that phenotypic comparisons between mice must take into account the non-chromosomal hereditary variation between different breeders. We propose faecal IgA as one marker of microbial variability and conclude that co-housing and/or faecal transplantation enables analysis of progeny from different dams.

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Change history

  • 06 May 2015

    The footnote symbols in Fig. 2d and Tukey’s P-value in the Figs 1-4 legends were corrected.


Primary accessions

European Nucleotide Archive

Data deposits

16S rDNA sequencing data have been deposited in the European Nucleotide Archive under accession number PRJEB7854.


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This work was supported by National Institutes of Health (NIH) grants AI08488702 and DK7161907, the Crohn’s & Colitis Foundation of America Genetics Initiative, the Rainin Foundation, and the Helmsley Charitable Trust. C.M. was supported by NIH training grant T32AI007163, and M.T.B. was supported by NIH training grant T32CA009547 and the W.M. Keck Fellowship from Washington University. We thank H. Miyoshi for technical recommendations, D. Kreamalmeyer for animal care and breeding, and members of the Stappenbeck and Virgin laboratories for discussion. Experimental support was provided by the Speed Congenics Facility of the Rheumatic Diseases Core Center (NIH award number P30AR048335) and the Digestive Disease Research Core Center (NIH award number P30DK052574) of Washington University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

    • Clara Moon
    •  & Megan T. Baldridge

    These authors contributed equally to this work.


  1. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA

    • Clara Moon
    • , Megan T. Baldridge
    • , Meghan A. Wallace
    • , Carey-Ann D. Burnham
    • , Herbert W. Virgin
    •  & Thaddeus S. Stappenbeck


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M.T.B. and C.M. designed the project, performed experiments, and wrote the paper. T.S.S. and H.W.V. assisted with project design and writing the paper. C.D.B. and M.A.W. assisted with microbial characterization and project design.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Herbert W. Virgin or Thaddeus S. Stappenbeck.

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