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High-affinity monoclonal IgA regulates gut microbiota and prevents colitis in mice

Abstract

Immunoglobulin A (IgA) is the main antibody isotype secreted into the intestinal lumen. IgA plays a critical role in the defence against pathogens and in the maintenance of intestinal homeostasis. However, how secreted IgA regulates gut microbiota is not completely understood. In this study, we isolated monoclonal IgA antibodies from the small intestine of healthy mouse. As a candidate for an efficient gut microbiota modulator, we selected a W27 IgA, which binds to multiple bacteria, but not beneficial ones such as Lactobacillus casei. W27 could suppress the cell growth of Escherichia coli but not L. casei in vitro, indicating an ability to improve the intestinal environment. Indeed W27 oral treatment could modulate gut microbiota composition and have a therapeutic effect on both lymphoproliferative disease and colitis models in mice. Thus, W27 IgA oral treatment is a potential remedy for inflammatory bowel disease, acting through restoration of host–microbial symbiosis.

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Figure 1: LP-derived monoclonal W27 antibody is identified as a high-affinity polyreactive IgA.
Figure 2: W27 IgA recognizes an epitope of the enzyme SHMT to selectively target a set of bacteria.
Figure 3: W27 suppressed E. coli cell growth via SHMT-specific recognition.
Figure 4: W27 oral treatment prevents pathological colonic phenotype and modulates gut microbial composition in AIDG23S mice.
Figure 5: W27 oral treatment prevents colitis induced by DSS and adoptive transfer of naive T cells.

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Acknowledgements

The authors thank T. Honjo for providing AIDG23S and AID−/− mice, Dr H. Niki for providing E. coli strains ME9062 and JW2535, S. Nomura and M. Ohta for technical help, and T. Nakano, K. Asoh and V. Shivarov for critical reading. This work was supported by grants from the Japan Science and Technology Agency, JSPS KAKENHI 15H04732, Yakult Bio-Science Foundation, Naito Memorial Foundation, Senshin Medical Research Foundation and Astellas Foundation for Research on Metabolic Disorders (to R.S.) and also by AMED-CREST, AMED and RIKEN Pioneering Project ‘Biology of Symbiosis’ (to H.O.).

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Authors and Affiliations

Authors

Contributions

S.Okai, F.U. and R.S. designed and performed experiments, analysed data and wrote the paper. S.Okai, S.Y., Y.H., T.N. and M.K. performed pathological analyses. S.M., M.N., T.N. and Y.W. provided live anaerobic bacteria and performed bacterial qPCR analysis. M.H. performed mass spectrometry. S.Okai, R.S., S.M., E.M. and H.O. were involved in induced colitis experiments. E.M. and H.O. performed W27 binding bacterial sorting and related bioinformatics analyses. T.K., H.O., K.Y., E.N., H.M., T.Y. and K.K. performed microbiome bioinformatics analyses for antibody-treated mice. S.Okada provided essential materials. S.Okai, F.U., R.S., S.M., H.O., K.K., H.M., E.M. and T.K. were involved in data discussions.

Corresponding author

Correspondence to Reiko Shinkura.

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The authors declare no competing financial interests.

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Supplementary information

Supplementary Tables 1–7, Supplementary Figures 1–6. (PDF 4433 kb)

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Okai, S., Usui, F., Yokota, S. et al. High-affinity monoclonal IgA regulates gut microbiota and prevents colitis in mice. Nat Microbiol 1, 16103 (2016). https://doi.org/10.1038/nmicrobiol.2016.103

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