Page 6 Acknowledgments We thank Drs. Elaine Hsiao, June Round, Hiutung Chu, and members of the Mazmanian laboratory for critical review of this manuscript. The anti-CD20 antibody was provided under an mTA from Genentech. We appreciat technical support from Taren Thron, the Caltech Office of Laboratory Animal Resources, Caltech Genomics Laboratory, and Caltech Flow Cytometry Facility. G.P.D. was supported by an NIH training grant(5T32 GM07616 and NSF Graduate Research Fellowship(DGE-1144469) Support for this research was provided by grants from the ational Institutes of Health to the Broad Institute(U19All 10818), the NIh(P50 GM82545 and A104 123)to P. B.J., the NIH (GM099535 and DK083633)to S K M., and the Heritage Medical Research Institute to S K M. All data and code to understand and assess the conclusions of this research are available in the main text, supplementary materials and via the following repositories: EMBL-EBI accession ERP107727 and NCBI Bioproject accessions PRNA445716 and PRJNA438372 References and Notes 1. Hall AB, Tolonen AC, Xavier RJ. Human genetic variation and the gut microbiome in disease. Nat Rev genet.2017;doi:10.1038/nrg.201763 2. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017, 20: 145-155. [PubMed 28092661] 3. Faith JJ, et al. The long-term stability of the human gut microbiota. Science. 2013: 341: 1237439 [PubMed: 238289411 4. Truong DT, Tett A, Pasolli E, Huttenhower C, Segata N. Microbial strain-level population structure and genetic diversity from metagenomes. Genome Res 2017 gr 216242 116 5. Fagarasan S, et al. Critical roles of activation -induced cytidine deaminase in the homeostasis of gut lora. Science.2002;298:1424-1427.[ Pubmed:12434060 6. Kawamoto S, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science.2012,336:485-489.[ PubMed:22539724] 7. Macpherson AJ, Koller Y, McCoy KD. The bilateral responsiveness between intestinal microbes and IgA. Trends Immunol. 2015; 36: 460-470.[PubMed: 26169256] 8. Kubinak JL, Round JL. Do antibodies select a healthy microbiota? Nat Rev Immunol. 2016 16:767774.[ PubMed:27818504] 9. Kubinak JL, et al. My D88 signaling in T cells directs Ig A-mediated control of the microbiota to promote health Cell Host Microbe 2015; 17: 153-163.[PubMed: 25620548 10. Fransen F, et al. BALB/c and C57BL/6 Mice Differ in Polyreactive IgA Abundance, which Impacts the Generation of Antigen-Specific IgA and Microbiota Diversity. Immunology. 2015; 43: 527- 11. Kawamoto S, et al. Foxp3(+)T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunology. 2014 41:152-165 12. Mantis NJ, Forbes SJ. Secretory IgA; arresting microbial pathogens at epithelial borders. Immunol Invest.2010,39:383-406.[ PubMed:20450284] 13. van der Waaij LA, Limburg PC, Mesander G, van der Waaij D. In vivo IgA coating of anaerobic bacteria in human faeces. Gut. 1996; 38: 348-354 PubMed: 8675085 14. Shroff KE, Meslin K, Cebra JJ. Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect Immun. 1995: 63: 3904- 13.[ PubMed:7558298] 15. Bollinger RR, et al. Human secretory immunoglobulin a may contribute to biofilm formation in the gut Immunology. 2003; 109: 580-587 [PubMed: 12871226] 16. Mathias A, et al. Potentiation of polarized intestinal Caco-2 cell responsiveness to probiotics complexed with secretory IgA. J Biol Chem. 2010, 285: 33906-33913 [PubMed: 207292111 17. Yel L Selective IgA deficiency. Journal of clinical immunology. 2010; doi: 10.1007/ s10875-009-9357X 18. Conley ME D. D. A O.I. medicine Intravascular and mucosal immunoglobulin A: two separat but related systems of immune defense? Am Coll Physicians. 1987; doi 10.7326/0003-4819-106-6-892 cience. Author manuscript; available in PMC 2018 November 18Acknowledgments We thank Drs. Elaine Hsiao, June Round, Hiutung Chu, and members of the Mazmanian laboratory for critical review of this manuscript. The anti-CD20 antibody was provided under an MTA from Genentech. We appreciate technical support from Taren Thron, the Caltech Office of Laboratory Animal Resources, Caltech Genomics Laboratory, and Caltech Flow Cytometry Facility. G.P.D. was supported by an NIH training grant (5T32 GM07616) and NSF Graduate Research Fellowship (DGE-1144469). Support for this research was provided by grants from the National Institutes of Health to the Broad Institute (U19AI110818), the NIH (P50 GM082545 and AI04123) to P.B.J., the NIH (GM099535 and DK083633) to S.K.M., and the Heritage Medical Research Institute to S.K.M. All data and code to understand and assess the conclusions of this research are available in the main text, supplementary materials and via the following repositories: EMBL-EBI accession ERP107727 and NCBI Bioproject accessions PRJNA445716 and PRJNA438372. References and Notes 1. Hall AB, Tolonen AC, Xavier RJ. Human genetic variation and the gut microbiome in disease. Nat Rev Genet. 2017; doi: 10.1038/nrg.2017.63 2. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017; 20:145–155. [PubMed: 28092661] 3. Faith JJ, et al. The long-term stability of the human gut microbiota. Science. 2013; 341:1237439. [PubMed: 23828941] 4. Truong DT, Tett A, Pasolli E, Huttenhower C, Segata N. Microbial strain-level population structure and genetic diversity from metagenomes. Genome Res. 2017 gr.216242.116. 5. Fagarasan S, et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science. 2002; 298:1424–1427. [PubMed: 12434060] 6. Kawamoto S, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science. 2012; 336:485–489. [PubMed: 22539724] 7. Macpherson AJ, Köller Y, McCoy KD. The bilateral responsiveness between intestinal microbes and IgA. Trends Immunol. 2015; 36:460–470. [PubMed: 26169256] 8. Kubinak JL, Round JL. Do antibodies select a healthy microbiota? Nat Rev Immunol. 2016; 16:767–774. [PubMed: 27818504] 9. Kubinak JL, et al. MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe. 2015; 17:153–163. [PubMed: 25620548] 10. Fransen F, et al. BALB/c and C57BL/6 Mice Differ in Polyreactive IgA Abundance, which Impacts the Generation of Antigen-Specific IgA and Microbiota Diversity. Immunology. 2015; 43:527– 540. 11. Kawamoto S, et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunology. 2014; 41:152–165. 12. Mantis NJ, Forbes SJ. Secretory IgA: arresting microbial pathogens at epithelial borders. Immunol Invest. 2010; 39:383–406. [PubMed: 20450284] 13. van der Waaij LA, Limburg PC, Mesander G, van der Waaij D. In vivo IgA coating of anaerobic bacteria in human faeces. Gut. 1996; 38:348–354. [PubMed: 8675085] 14. Shroff KE, Meslin K, Cebra JJ. Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect Immun. 1995; 63:3904– 3913. [PubMed: 7558298] 15. Bollinger RR, et al. Human secretory immunoglobulin A may contribute to biofilm formation in the gut. Immunology. 2003; 109:580–587. [PubMed: 12871226] 16. Mathias A, et al. Potentiation of polarized intestinal Caco-2 cell responsiveness to probiotics complexed with secretory IgA. J Biol Chem. 2010; 285:33906–33913. [PubMed: 20729211] 17. Yel L. Selective IgA deficiency. Journal of clinical immunology. 2010; doi: 10.1007/ s10875-009-9357-x 18. Conley ME. D. D. A. O. I. medicine. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Am Coll Physicians. 1987; doi: 10.7326/0003-4819-106-6-892 Donaldson et al. Page 6 Science. Author manuscript; available in PMC 2018 November 18. Author Manuscript Author Manuscript Author Manuscript Author Manuscript