ABSTRACT 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

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. Access through your institution Buy or subscribe This is a preview of subscription content,

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MICROBIOME OF C57BL/6 MICE FROM DIFFERENT VENDORS AND PRODUCTION SITES, AND IN RESPONSE TO A NEW VIVARIUM Article 14 June 2021 GENETIC MAPPING OF MICROBIAL AND HOST TRAITS REVEALS PRODUCTION

OF IMMUNOMODULATORY LIPIDS BY _AKKERMANSIA MUCINIPHILA_ IN THE MURINE GUT Article Open access 09 February 2023 TRANSFER EFFICIENCY AND IMPACT ON DISEASE PHENOTYPE OF DIFFERING METHODS OF

GUT MICROBIOTA TRANSFER Article Open access 15 November 2022 ACCESSION CODES PRIMARY ACCESSIONS EUROPEAN NUCLEOTIDE ARCHIVE * PRJEB7854 DATA DEPOSITS 16S rDNA sequencing data have been

deposited in the European Nucleotide Archive under accession number PRJEB7854. CHANGE HISTORY * _ 06 MAY 2015 The footnote symbols in Fig. 2d and Tukey’s P-value in the Figs 1-4 legends were

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ImageJ: 25 years of image analysis. _Nature Methods_ 9, 671–675 (2012) Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS 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. AUTHOR INFORMATION

Author notes * Clara Moon and Megan T. Baldridge: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Pathology and Immunology, Washington University

School of Medicine, St Louis, 63110, Missouri, USA Clara Moon, Megan T. Baldridge, Meghan A. Wallace, Carey-Ann D. Burnham, Herbert W. Virgin & Thaddeus S. Stappenbeck Authors * Clara

Moon View author publications You can also search for this author inPubMed Google Scholar * Megan T. Baldridge View author publications You can also search for this author inPubMed Google

Scholar * Meghan A. Wallace View author publications You can also search for this author inPubMed Google Scholar * Carey-Ann D. Burnham View author publications You can also search for this

author inPubMed Google Scholar * Herbert W. Virgin View author publications You can also search for this author inPubMed Google Scholar * Thaddeus S. Stappenbeck View author publications You

can also search for this author inPubMed Google Scholar CONTRIBUTIONS 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. CORRESPONDING AUTHORS Correspondence to Herbert W. Virgin or Thaddeus S.

Stappenbeck. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. EXTENDED DATA FIGURES AND TABLES EXTENDED DATA FIGURE 1 WT MICE WITHIN TWO

INDEPENDENT FACILITIES EXHIBIT BINARY FAECAL IGA LEVELS, AND THE IGA-LOW PHENOTYPE IS TRANSFERABLE BETWEEN THESE FACILITIES. A, Faecal IgA (normalized to faecal weight) from mice housed in

either facility 1 (_n_ = 28 IgA-high and _n_ = 22 IgA-low mice) or facility 2 (_n_ = 12 mice per group) was detected by anti-mouse IgA ELISA. B, C, WT IgA-high mice from one mouse facility

were transplanted with homogenized faecal material from WT IgA-high or IgA-low mice from the other mouse facility, and faecal IgA was measured 14 days later by anti-mouse IgA ELISA. B,

Facility 1 mice pre- (_n_ = 18 mice) and post-faecal transplantation with facility 2 faecal samples (_n_ = 8 post-IgA-high and _n_ = 10 post-IgA-low mice). C, Facility 2 mice pre- (_n_ = 10

mice) and post-faecal transplantation with facility 1 faecal samples (_n_ = 4 post-IgA-high and _n_ = 6 post-IgA-low mice). The dotted lines represent the limit of detection by ELISA. All

values are mean ± s.e.m. One-way ANOVA: A, _F_ = 44.59, _P_ < 0.0001; B, _F_ = 20.93, _P_ < 0.0001; C, _F_ = 12.92, _P_ = 0.0004. Means with different footnote symbols are

significantly different by Tukey’s multiple comparison test (_P_ < 0.5). EXTENDED DATA FIGURE 2 IGA-HIGH- AND IGA-LOW-ASSOCIATED MICROBES CAN BE STABLY PASSAGED THROUGH _PIGR_−/−

RECIPIENTS, AND ARE VERTICALLY TRANSMISSIBLE AFTER RECOLONIZATION. A, Schematic for repopulation of _pIgR__−/−_ microbiota with WT IgA-high/IgA-low samples, followed by faecal

transplantation (FT) of _pIgR__−/−_ IgA-high or IgA-low samples to WT IgA-high mice. B, Faecal IgA on day 44 depicted in A. Mann–Whitney _U_-test: _P_ = 0.0006, _n_ = 8 mice per group. C,

Experimental schematic of antibiotic treatment and transplant protocol for D and Fig. 1f, g. D, Faecal IgA of post-FT mice on day 30 pre-treated with metronidazole (Metro). One-way ANOVA:

_F_ = 6.525, _P_ = 0.0012, _n_ = 13 (pre-Metro), _n_ = 15 (post-Metro), _n_ = 8 (post-IgA-high FT), and _n_ = 5 (post-IgA-low FT). All values are mean ± s.e.m. E, IgA-low mice converted to

IgA-high from Fig. 1f were mated, and faecal IgA of their adult progeny was measured. One-way ANOVA: _F_ = 18.29, _P_ = 0.0002, _n_ = 2 breeders, _n_ = 10 progeny from four litters.

Different footnote symbols indicate groups significantly different by Tukey's multiple comparison test (_P_ < 0.5). Dotted lines: limit of detection. EXTENDED DATA FIGURE 3 DSS

EFFECTS ON _PIGR__−/−_ MICE ARE DEPENDENT ON IGA AND NOT MICROBES. A, Faecal IgA levels were measured in WT mice from Fig. 2d, e after VNAM treatment and IgA-high/IgA-low faecal

transplantation (FT), before the start of DSS treatment. Statistical analysis by Mann–Whitney _U_-test: _P_ = 0.0006, _n_ = 7 mice per group. B, Representative haematoxylin and eosin-stained

histological sections of WT and _pIgR__−/−_ mice from Fig. 2d, e after 14 day VNAM treatment + IgA-high/IgA-low faecal transplantation. Representative of _n_ = 3 (WT + IgA-high), _n_ = 6

(WT + IgA-low), _n_ = 8 (_pIgR__−/−_ + IgA-high), and _n_ = 10 (_pIgR__−/−_ + IgA-low) mice. All values indicated as mean ± s.e.m. Means with different footnote symbols are significantly

different by Tukey’s multiple comparison test (_P_ < 0.5). Dotted lines, limit of detection. EXTENDED DATA FIGURE 4 PLASMA CELL NUMBERS AND PIGR EXPRESSION ARE UNCHANGED IN THE ILEUM AND

COLON BETWEEN IGA-HIGH AND IGA-LOW MICE. A–D, Ileal and colonic sections from IgA-high and IgA-low mice were stained with anti-IgA (green) and bis-benzamide dye (blue); representative ×20

images are shown of _n_ = 10 (A–C) or _n_ = 9 mice (D). Scale bars, 100 μm. E, F, Quantification of ileal plasma cells per villus (E) and colonic plasma cells per ×20 field (area = 1.5 μm ×

105 μm) (F) based on IgA staining. All values are mean ± s.e.m. Statistical analysis by Mann–Whitney _U_-test: E, _P_ = 0.5191, _n_ = 10 mice per group; F, _P_ = 0.3117, _n_ = 10 IgA-high

and _n_ = 9 IgA-low mice. G–J, Ileal and colonic sections from IgA-high and IgA-low mice were stained with anti-pIgR/secretory component (red) and bis-benzamide dye (blue); representative

images are shown (_n_ = 10 mice per group). Scale bars, 100 μm. EXTENDED DATA FIGURE 5 16S RDNA SEQUENCING IDENTIFIES BIOMARKERS FOR IGA-LOW AND IGA-HIGH SAMPLES. A, B, LEfSe analysis31 of

16S rDNA sequencing of IgA-low and IgA-high faecal samples from facilities 1 and 2 identified statistically significant bacterial taxa biomarkers for (A) IgA-low and (B) IgA-high samples.

Biomarkers for facility 1 and biomarkers for facility 2 alone were identified by comparison of IgA-high and IgA-low samples within each facility. Biomarkers for facilities 1 and 2 were

identified by comparison of all IgA-high and IgA-low samples from both facilities. No IgA-high biomarkers were identified when comparing all IgA-high and IgA-low samples from both

facilities. Biomarkers for the indicated groups are plotted as taxonomic trees with GraPhlAn (http://huttenhower.sph.harvard.edu/graphlan); _n_ = 13 (facility 1 IgA-high), _n_ = 14 (facility

1 IgA-low), _n_ = 73 (facility 2 IgA-high), and _n_ = 68 (facility 2 IgA-low) samples. Statistical analysis is shown in Extended Data Table 1. EXTENDED DATA FIGURE 6 _SUTTERELLA_ IS MORE

ABUNDANT IN IGA-LOW SAMPLES THAN IGA-HIGH SAMPLES IN BOTH FACILITIES. A–C, Relative abundance of sequences assigned by QIIME to the bacterial genus _Sutterella_ from 16S rDNA analysis in (A)

facility 1 and (B) facility 2. These results are summarized in C. One-way ANOVA: _F_ = 12.85, _P_ < 0.0001. _n_ = 13 (facility 1 IgA-high), _n_ = 14 (facility 1 IgA-low), _n_ = 73

(facility 2 IgA-high), and _n_ = 68 (facility 2 IgA-low) samples. Values in C are indicated as mean ± s.e.m. Means with different footnote symbols are significantly different by Tukey’s

multiple comparison test (_P_ < 0.5). EXTENDED DATA FIGURE 7 IGA-LOW CULTURED BACTERIA CAN DEGRADE FREE SECRETORY COMPONENT IN THE ABSENCE OF IGA, AND SECRETORY-COMPONENT-DEGRADING

PROPERTIES OF THESE BACTERIA ARE ACTIVE AFTER FREEZE/THAW. Primary intestinal epithelial Transwell monolayers were pre-treated with 10 μM DAPT + 1 μg ml−1 LPS on days 1 and 2 post-seeding to

induce differentiation and pIgR expression. Some wells were left untreated as negative controls. On day 3 post-seeding, either 3 μg of normal mouse dimeric IgA or media alone was added to

the lower compartment of the Transwells. Different subsets of the DAPT + LPS-treated Transwells were also treated with one of the following conditions in the apical compartment:

IgA-high/IgA-low bacterial cultures (pelleted bacterial or supernatant fraction), live or freeze/thawed IgA-high/IgA-low bacterial cultures (pelleted bacterial fraction). Apical Transwell

supernatants were collected at 3 h and 6 h, and the amount of secretory component was measured by anti-secretory-component immunoblot. A, Representative anti-pIgR/secretory component and

anti-actin immunoblots of intestinal epithelial monolayers at 6 h (one of three experiments). B–D, Secretory component degradation in the absence of IgA. (B) Representative

anti-secretory-component immunoblot and quantification of undegraded secretory component (denoted by the red brackets) at 3 h (C) and 6 h (D) over four independent experiments by ImageJ.

E–G, Secretory component degradation by freeze/thawed bacterial cultures. E, Representative anti-secretory-component immunoblot and quantification of undegraded secretory component at 3 h

(F) and 6 h (G) over five independent experiments by ImageJ. All values are mean ± s.e.m. One-way ANOVA: C, _F_ = 1.834, _P_ = 0.1831, _n_ = 4 independent experiments with DAPT + LPS, no IgA

repeated twice; D, _F_ = 23.96, _P_ = 0.0002, _n_ = 4 independent experiments with DAPT + LPS, no IgA repeated twice; F, _F_ = 7.444, _P_ = 0.0045, _n_ = 5 independent experiments with

untreated and DAPT + LPS repeated three times; G, _F_ = 31.53, _P_ < 0.0001, _n_ = 5 independent experiments with untreated and DAPT + LPS repeated three times. Means with different

footnote symbols are significantly different by Tukey’s multiple comparison test (_P_ < 0.5). EXTENDED DATA FIGURE 8 IGA-LOW CULTURED BACTERIA CAN DEGRADE IGA. Primary intestinal

epithelial cell monolayers were pre-treated with 10 μM DAPT + 1 μg ml−1 LPS on days 1 and 2 post-seeding to induce differentiation and pIgR expression. Some wells were left untreated as

negative controls. On day 3 post-seeding, 3 μg of normal mouse IgA was added to the lower compartment of the Transwells. Different subsets of the DAPT + LPS-treated Transwells were also

treated with combinations of the following in the apical compartment: live IgA-low bacterial cultures (either the pelleted bacterial or supernatant fraction), freeze/thawed IgA-low bacterial

cultures, and a 1× protease inhibitor (PI) cocktail. Apical Transwell supernatants were collected at 3 h (A) and 6 h (B), and the amount of IgA was measured by anti-mouse IgA ELISA. The

dotted lines represent the limit of detection by ELISA. All values are mean ± s.e.m. One-way ANOVA: A, _F_ = 26.32, _P_ < 0.0001, _n_ = 8 (untreated), _n_ = 8 (DAPT + LPS), _n_ = 6

(IgA-low culture, pellet), _n_ = 3 (IgA-low culture, supernatant), _n_ = 4 (IgA-low culture, freeze/thawed), and _n_ = 4 (IgA-low culture, +PI); B, _F_ = 35.57, _P_ < 0.0001, _n_ = 8

(untreated), _n_ = 8 (DAPT + LPS), _n_ = 6 (IgA-low culture, pellet), _n_ = 3 (IgA-low culture, sup), _n_ = 3 (IgA-low culture, freeze/thawed), and _n_ = 4 (IgA-low culture, +PI). Means with

different footnote symbols are significantly different by Tukey’s multiple comparison test (_P_ < 0.5); ND, not detected. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE

FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Moon, C., Baldridge, M., Wallace, M.

_et al._ Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. _Nature_ 521, 90–93 (2015). https://doi.org/10.1038/nature14139 Download citation *

Received: 18 June 2014 * Accepted: 03 December 2014 * Published: 16 February 2015 * Issue Date: 07 May 2015 * DOI: https://doi.org/10.1038/nature14139 SHARE THIS ARTICLE Anyone you share the

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