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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References
Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
Huttenhower, C., Kostic, A. D. & Xavier, R. J. Inflammatory bowel disease as a model for translating the microbiome. Immunity 40, 843–854 (2014).
Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009).
Brandtzaeg, P. Secretory IgA: designed for anti-microbial defense. Front. Immunol. 4, 222 (2013).
Macpherson, A. J. & McCoy, K. D. Independence day for IgA. Immunity 43, 416–418 (2015).
Pabst, O. New concepts in the generation and functions of IgA. Nature Rev. Immunol. 12, 821–832 (2012).
Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014).
Mantis, N. J., Rol, N. & Corthesy, B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 4, 603–611 (2011).
Brandtzaeg, P., Fjellanger, I. & Gjeruldsen, S. T. Adsorption of immune A onto oral bacteria in vivo. J. Bacteriol. 96, 242–249 (1968).
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, 276ra224 (2015).
Fagarasan, S. et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 298, 1424–1427 (2002).
Wei, M. et al. Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense. Nature Immunol. 12, 264–270 (2011).
Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).
Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15, 382–392 (2014).
Andoh, A. et al. Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn's disease. J. Gastroenterol. 47, 1298–1307 (2012).
Lasserre, J. P. et al. A complexomic study of Escherichia coli using two-dimensional blue native/SDS polyacrylamide gel electrophoresis. Electrophoresis 27, 3306–3321 (2006).
Link, A. J., Robison, K. & Church, G. M. Comparing the predicted and observed properties of proteins encoded in the genome of Escherichia coli K-12. Electrophoresis 18, 1259–1313 (1997).
Weiner, J. H. & Li, L. Proteome of the Escherichia coli envelope and technological challenges in membrane proteome analysis. Biochim. Biophys. Acta 1778, 1698–1713 (2008).
Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006.0008 (2006).
Nichols, R. J. et al. Phenotypic landscape of a bacterial cell. Cell 144, 143–156 (2011).
Matsuki, T. et al. Quantitative PCR with 16S rRNA-gene-targeted species-specific primers for analysis of human intestinal bifidobacteria. Appl. Environ. Microbiol. 70, 167–173 (2004).
Cooper, H. S., Murthy, S. N., Shah, R. S. & Sedergran, D. J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Invest. 69, 238–249 (1993).
Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).
Mathias, A. & Corthesy, B. Recognition of gram-positive intestinal bacteria by hybrid- and colostrum-derived secretory immune A is mediated by carbohydrates. J. Biol. Chem. 286, 17239–17247 (2011).
Ono, A. et al. Comparative study of human hematopoietic cell engraftment into BALB/c and C57BL/6 strain of rag-2/jak3 double-deficient mice. J. Biomed. Biotechnol. 2011, 539748 (2011).
Morita, H. et al. An improved DNA isolation method for metagenomic analysis of the microbial flora of the human intestine. Microbes Environ. 22, 214–222 (2007).
Kozich, J. J., Westcott, S. L., Baxter, N. T., Highlander, S. K. & Schloss, P. D. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl. Environ. Microbiol. 79, 5112–5120 (2013).
Edgar, R. C., Haas, B. J., Clemente, J. C., Quince, C. & Knight, R. UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27, 2194–2200 (2011).
Matsuda, K., Tsuji, H., Asahara, T., Kado, Y. & Nomoto, K. Sensitive quantitative detection of commensal bacteria by rRNA-targeted reverse transcription-PCR. Appl. Environ. Microbiol. 73, 32–39 (2007).
Matsuki, T., Watanabe, K., Fujimoto, J., Takada, T. & Tanaka, R. Use of 16S rRNA gene-targeted group-specific primers for real-time PCR analysis of predominant bacteria in human feces. Appl. Environ. Microbiol. 70, 7220–7228 (2004).
Rinttila, T., Kassinen, A., Malinen, E., Krogius, L. & Palva, A. Development of an extensive set of 16S rDNA-targeted primers for quantification of pathogenic and indigenous bacteria in faecal samples by real-time PCR. J. Appl. Microbiol. 97, 1166–1177 (2004).
Cole, J. R. et al. Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic Acids Res. 42, D633–D642 (2014).
Quast, C. et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 41, D590–D596 (2013).
Walter, J. et al. Detection and identification of gastrointestinal Lactobacillus species by using denaturing gradient gel electrophoresis and species-specific PCR primers. Appl. Environ. Microbiol. 66, 297–303 (2000).
Osek, J. Development of a multiplex PCR approach for the identification of Shiga toxin-producing Escherichia coli strains and their major virulence factor genes. J. Appl. Microbiol. 95, 1217–1225 (2003).
Schmieder, R., Lim, Y. W., Rohwer, F. & Edwards, R. TagCleaner: identification and removal of tag sequences from genomic and metagenomic datasets. BMC Bioinformatics 11, 341 (2010).
Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261–5267 (2007).
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nature Methods 9, 357–359 (2012).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cell. Nature 504, 446–450 (2013).
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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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.
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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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DOI: https://doi.org/10.1038/nmicrobiol.2016.103
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