Beyond B. fragilis, we tested whether IgA shapes a complex microbiome following controlled introduction of mouse microbiota to germ-free BALB/c or IgA--miceOne month following colonization, despite similar microbiome profiles in feces of both mouse genotypes(fig. S8A), we observed differences for specific taxa(Table S3). We also identified a defect in community stratification between the colonic mucus and lumen of IgA mice(Fig. 4H and S8B), revealing that Iga is required to individualize microbiome profiles between these two anatomic locations. Remarkably, a highly mucus-enriched exact equence variant(ESV), mapping uniquely to B. fragilis, was significantly decreased in the mucus ofIgA mice compared to BALB/c mice( Fig. 4I and S9A), naturally supporting our observations from mono-colonized mice. To extend this analysis to other microbial species, we identified Rikanellaceae, Blautia sp, and segmented filamentous bacteria(SFB as being highly IgA-coated (fig. S9B)(35), and assessed the abundance of these taxa in the colonic or ileal mucus. Blautia sp and segmented filamentous bacteria(SFB)displayed increased mucosal association in the absence of IgA(Fig. 41)(42), demonstrating that IgA 于9之 can protect the intestinal barrier. However, similar to B. fragilis, Rikanellaceae were highly abundant in colon mucus and significantly depleted in IgA mice( Fig. 4D). We conclude that IgA-enhanced mucosal colonization occurs within complex communities for multiple strains of B. fragilis and other species of the gut microbiome Classically viewed, the immune system evolved to prevent microbial colonization. However, not only do animals tolerate a complex microbiome, in the case of B. fragilis provoking an immune response paradoxically enables intimate association with its mammalian host Related commensal bacteria may also benefit from actively engaging IgA during symbiosis. as Rag2/- mice devoid of adaptive immunity harbor fewer Bacteroides(43), and both B cell deficient and IgA- animals display decreased colonization by the Bacteroidaceae family (44). IgA has been previously shown to increase adherence of Escherichia coli(15) Bifidobacterium lactis, and Lactobacillus ramnosus(16)to tissue-cultured epithelial cells, suggesting that these microorganisms may also benefit from IgA to establish a mucosal bacterial community. Mucosal microbiome instability or loss of immunomodulatory species may underlie the link between Iga deficiency and autoimmune diseases in humans(45) Interestingly, while IgA-coated bacteria from individuals with IBD (46)or nutritional deficiencies(47)exacerbate respective pathologies in mice, IgA-coated bacteria from healthy humans protect mice from disease(47). We propose that during health, IgA fosters mucosal colonization of microbiota with beneficial properties(9), while disease states ma induce(or be caused by IgA responses to pathogens or pathobionts that disrupt health microbiome equilibria. Indeed, computational models indicate that IgA can both maintain indigenous mucosal populations and clear invasive pathogens (48). In addition to serving a defense system, we discover that adaptive immunity evolved to engender intimate association with members of the gut microbiome Supplementary Material Refer to Web version on PubMed Central for supplementary material cience. Author manuscript; available in PMC 2018 November 18Beyond B. fragilis, we tested whether IgA shapes a complex microbiome following controlled introduction of mouse microbiota to germ-free BALB/c or IgA−/− mice. One month following colonization, despite similar microbiome profiles in feces of both mouse genotypes (fig. S8A), we observed differences for specific taxa (Table S3). We also identified a defect in community stratification between the colonic mucus and lumen of IgA −/− mice (Fig. 4H and S8B), revealing that IgA is required to individualize microbiome profiles between these two anatomic locations. Remarkably, a highly mucus-enriched exact sequence variant (ESV), mapping uniquely to B. fragilis, was significantly decreased in the mucus of IgA−/− mice compared to BALB/c mice (Fig. 4I and S9A), naturally supporting our observations from mono-colonized mice. To extend this analysis to other microbial species, we identified Rikanellaceae, Blautia sp., and segmented filamentous bacteria (SFB) as being highly IgA-coated (fig. S9B) (35), and assessed the abundance of these taxa in the colonic or ileal mucus. Blautia sp. and segmented filamentous bacteria (SFB) displayed increased mucosal association in the absence of IgA (Fig. 4I) (42), demonstrating that IgA can protect the intestinal barrier. However, similar to B. fragilis, Rikanellaceae were highly abundant in colon mucus and significantly depleted in IgA−/− mice (Fig. 4I). We conclude that IgA-enhanced mucosal colonization occurs within complex communities for multiple strains of B. fragilis and other species of the gut microbiome. Classically viewed, the immune system evolved to prevent microbial colonization. However, not only do animals tolerate a complex microbiome, in the case of B. fragilis provoking an immune response paradoxically enables intimate association with its mammalian host. Related commensal bacteria may also benefit from actively engaging IgA during symbiosis, as Rag2 −/− mice devoid of adaptive immunity harbor fewer Bacteroides (43), and both B cell deficient and IgA−/− animals display decreased colonization by the Bacteroidaceae family (44). IgA has been previously shown to increase adherence of Escherichia coli (15), Bifidobacterium lactis, and Lactobacillus ramnosus (16) to tissue-cultured epithelial cells, suggesting that these microorganisms may also benefit from IgA to establish a mucosal bacterial community. Mucosal microbiome instability or loss of immunomodulatory species may underlie the link between IgA deficiency and autoimmune diseases in humans (45). Interestingly, while IgA-coated bacteria from individuals with IBD (46) or nutritional deficiencies (47) exacerbate respective pathologies in mice, IgA-coated bacteria from healthy humans protect mice from disease (47). We propose that during health, IgA fosters mucosal colonization of microbiota with beneficial properties (9), while disease states may induce (or be caused by) IgA responses to pathogens or pathobionts that disrupt healthy microbiome equilibria. Indeed, computational models indicate that IgA can both maintain indigenous mucosal populations and clear invasive pathogens (48). In addition to serving as a defense system, we discover that adaptive immunity evolved to engender intimate association with members of the gut microbiome. Supplementary Material Refer to Web version on PubMed Central for supplementary material. Donaldson et al. Page 5 Science. Author manuscript; available in PMC 2018 November 18. 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