IgA mediates microbial homeostasis at the intestinal mucosa. Within the gut, IgA acts in a context-dependent manner to both prevent and promote bacterial colonization and to influence bacterial gene expression, thus providing exquisite control of the microbiota. IgA–microbiota interactions are highly diverse across individuals and populations, yet the factors driving this variation remain poorly understood. In this Review, we summarize evidence for the host, bacterial and environmental factors that influence IgA–microbiota interactions. Recent advances have helped to clarify the antigenic specificity and immune selection of intestinal IgA and have highlighted the importance of microbial glycan recognition. Furthermore, emerging evidence suggests that diet and nutrition play an important role in shaping IgA recognition of the microbiota. IgA–microbiota interactions are disrupted during both overnutrition and undernutrition and may be altered dynamically in response to diet, with potential implications for host health. We situate this research in the context of outstanding questions and future directions in order to better understand the fascinating paradigm of IgA–microbiota homeostasis.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gopalakrishna, K. P. et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat. Med. 25, 1110–1115 (2019).
Mirpuri, J. et al. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes 5, 28–39 (2014).
Rogier, E. W. et al. Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. Proc. Natl Acad. Sci. USA 111, 3074 (2014).
Zheng, W. et al. Microbiota-targeted maternal antibodies protect neonates from enteric infection. Nature 577, 543–548 (2020).
Janzon, A. et al. Interactions between the gut microbiome and mucosal immunoglobulins A, M, and G in the developing infant gut. mSystems https://doi.org/10.1128/mSystems.00612-19 (2019).
Lindner, C. et al. Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. J. Exp. Med. 209, 365–377 (2012).
Planer, J. D. et al. Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice. Nature 534, 263–266 (2016).
Dzidic, M. et al. Aberrant IgA responses to the gut microbiota during infancy precedes asthma and allergy development. J. Allergy. Clin. Immunol. https://doi.org/10.1016/j.jaci.2016.06.047 (2016).
Alipour, M. et al. Mucosal barrier depletion and loss of bacterial diversity are primary abnormalities in paediatric ulcerative colitis. J. Crohn’s Colitis 10, 462–471 (2016).
Macpherson, A., Khoo, U. Y., Forgacs, I., Philpott-Howard, J. & Bjarnason, I. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 38, 365–375 (1996).
Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014). This fundamental study is one of the first to use IgA-SEQ and to demonstrate differences in IgA coating of pathobionts in patients with IBD.
Rengarajan, S. et al. Dynamic immunoglobulin responses to gut bacteria during inflammatory bowel disease. Gut Microbes 11, 405–420 (2019).
Viladomiu, M. et al. IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent inflammation. Sci. Transl Med. 9, eaaf9655 (2017).
Bridgman, S. L. et al. High fecal IgA is associated with reduced Clostridium difficile colonization in infants. Microbes Infect. 18, 543–549 (2016).
Jorgensen, G. H. et al. Clinical symptoms in adults with selective IgA deficiency: a case-control study. J. Clin. Immunol. 33, 742–747 (2013).
Koskinen, S. Long-term follow-up of health in blood donors with primary selective IgA deficiency. J. Clin. Immunol. 16, 165–170 (1996).
Huus, K. E. et al. Commensal bacteria modulate immunoglobulin a binding in response to host nutrition. Cell Host Microbe 27, 909–921 (2020). This paper shows that dietary adaptations in intestinal commensals can affect their IgA-binding ability, resulting in altered IgA–bacteria interactions during dietary shifts.
Huus, K. E. et al. Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study. Microbiome 8, 113 (2020).
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, 276ra24 (2015). This landmark paper shows that acute undernutrition in children is characterized by increased IgA recognition of pathogenic Proteobacteria but decreased recognition of other commensals; further, IgA+ Proteobacteria exacerbates undernutrition and enteropathy in mice.
Petersen, C. et al. T cell-mediated regulation of the microbiota protects against obesity. Science 365, eaat9351 (2019). This paper demonstrates that genetic defects in microbiota IgA targeting exacerbate obesity in mice by altering microbiota colonization patterns.
Jackson, K. J. L., Kidd, M. J., Wang, Y. & Collins, A. M. The shape of the lymphocyte receptor repertoire: lessons from the B cell receptor. Front. Immunol. 4, 263 (2013).
Mathias, A. & Corthésy, B. Recognition of Gram-positive intestinal bacteria by hybridoma- and colostrum-derived secretory immunoglobulin a is mediated by carbohydrates. J. Biol. Chem. 286, 17239–17247 (2011).
Day, C. J. et al. Glycan:glycan interactions: high affinity biomolecular interactions that can mediate binding of pathogenic bacteria to host cells. Proc. Natl Acad. Sci. USA 112, E7266–E7275 (2015).
Bovenkamp, F. S. van de et al. Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc. Natl Acad. Sci. USA 115, 1901–1906 (2018).
Bunker, J. J. et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358, eaan6619 (2017).
Grasset, E. K. et al. Gut T cell-independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells. Sci. Immunol. 5, eaat7117 (2020). This paper elegantly differentiates between T cell-dependent and T cell-independent IgA responses in mice, showing that both contribute to IgA coating of the microbiota but that T cell-independent responses do not measurably affect microbiota composition.
Chen, H. et al. BCR selection and affinity maturation in Peyer’s patch germinal centres. Nature 582, 421–425 (2020). One of three recent papers (along with Nowosad et al. and Li et al.) to study the emergence of the B cell repertoire in intestinal Peyer’s patches; finding that certain ‘public’ clones with microbiota and glycan reactivity emerge repeatedly in independent mice.
Zhang, B. et al. Divergent T follicular helper cell requirement for IgA and IgE production to peanut during allergic sensitization. Sci. Immunol. 5, eaay2754 (2020).
Kubinak, J. L. et al. MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe 17, 153–163 (2015).
Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. Immunity 43, 541–553 (2015).
Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364, 1179–1184 (2019).
Benckert, J. et al. The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific. J. Clin. Invest. 121, 1946–1955 (2011).
Kabbert, J. et al. High microbiota reactivity of adult human intestinal IgA requires somatic mutations. J. Exp. Med. 217, e20200275 (2020). This key study (alongside Sterlin et al.) defines the cross-species reactivity of human intestinal IgA clones and shows that it is dependent on somatic hypermutation, and not polyreactivity. This work further compares the binding capability of intestinal IgA from people with and without IBD.
Chen, J. W. et al. Autoreactivity in naïve human fetal B cells is associated with commensal bacteria recognition. Science 369, 320–325 (2020).
Nowosad, C. R. et al. Tunable dynamics of B cell selection in gut germinal centres. Nature 588, 321–326 (2020). One of three recent papers (alongside Chen et al. (Nature, 2020) and Li et al.) to study the emergence of the B cell repertoire in intestinal Peyer’s patches. This study demonstrates a greater expansion of public clones in germ-free mice than in microbiota-colonized mice.
Li, H. et al. Mucosal or systemic microbiota exposures shape the B cell repertoire. Nature 584, 274–278 (2020). One of three recent papers (alongside Chen et al. (Nature, 2020) and Nowosad et al.) to study the emergence of the B cell repertoire in intestinal Peyer’s patches. This study compares intestinal and systemic IgA responses to show that SIgA targets surface antigens and remains relatively less diverse than systemic antibody.
James, K. R. & King, H. W. Germs and germlines: how “public” B-cell clones evolve in the gut. Immunol. Cell Biol. 98, 428–430 (2020).
Pabst, O. & Slack, E. IgA and the intestinal microbiota: the importance of being specific. Mucosal Immunol. 13, 12–21 (2020).
Sterlin, D. et al. Human IgA binds a diverse array of commensal bacteriaHuman IgA binds a wide array of commensals. J. Exp. Med. 217, e20181635 (2020). This key study (alongside Kabbert et al.) defines cross-species reactivity of human intestinal IgA clones. The authors demonstrate that SIgA has specific glycan-binding profiles for surface bacterial structures; they further delineate the microbiota specificity of human IgA1 and IgA2 responses throughout development.
Cullender, T. C. et al. Innate and adaptive immunity interact to quench microbiome flagellar motility in the gut. Cell Host Microbe 14, 571–581 (2013).
Bunker, J. J. et al. B cell superantigens in the human intestinal microbiota. Sci. Transl Med. 11, eaau9356 (2019). This paper demonstrates that human commensal Lachnospiraceae produce IgA superantigens.
Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360, 795–800 (2018). This landmark paper demonstrates that IgA could directly promote mucosal colonization of commensal Bacteroides.
Nakajima, A. et al. IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria. J. Exp. Med. 215, 2019–2034 (2018). This study demonstrates that glycosylated SIgA regulated a PUL in Bacteroides, affecting inter-bacterial metabolic cooperation.
Naughton, J. A. et al. Divergent mechanisms of interaction of Helicobacter pylori and Campylobacter jejuni with mucus and mucins. Infect. Immun. 81, 2838–2850 (2013).
Garfias-López, J. A. et al. Immunization with intestinal microbiota-derived Staphylococcus aureus and Escherichia coli reduces bacteria-specific recolonization of the intestinal tract. Immunol. Lett. 196, 149–154 (2018).
Hendrickx, A. P. A. et al. Antibiotic-driven dysbiosis mediates intraluminal agglutination and alternative segregation of Enterococcus faecium from the intestinal epithelium. mBio 6, e01346–15 (2015).
Moor, K. et al. Peracetic acid treatment generates potent inactivated oral vaccines from a broad range of culturable bacterial species. Front. Immunol. 7, 37 (2016).
Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498–502 (2017).
Flannigan, K. L. & Denning, T. L. Segmented filamentous bacteria-induced immune responses: a balancing act between host protection and autoimmunity. Immunology 154, 537–546 (2018).
Lécuyer, E. et al. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity 40, 608–620 (2014).
Melo-Gonzalez, F. et al. Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria. J. Exp. Med. 216, 728–742 (2019).
Catanzaro, J. R. et al. IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM. Sci. Rep. 9, 13574 (2019).
Fadlallah, J. et al. Microbial ecology perturbation in human IgA deficiency. Sci. Transl Med. 16, eaan1217 (2018). This key paper shows that IgA deficiency in humans is characterized by both loss and gain of specific IgA-recognized intestinal bacteria.
Jørgensen, S. F. et al. Selective IgA deficiency in humans is associated with reduced gut microbial diversity. J. Allergy Clin. Immunol. 143, 1969–1971 (2019).
Kubinak, J. L. & Round, J. L. Do antibodies select a healthy microbiota? Nat. Rev. Immunol. 16, 767–774 (2016).
McLoughlin, K., Schluter, J., Rakoff-Nahoum, S., Smith, A. L. & Foster, K. R. Host selection of microbiota via differential adhesion. Cell Host Microbe 19, 550–559 (2016).
Hoces, D., Arnoldini, M., Diard, M., Loverdo, C. & Slack, E. Growing, evolving and sticking in a flowing environment: understanding IgA interactions with bacteria in the gut. Immunology 159, 52–62 (2020).
Bansept, F. et al. Enchained growth and cluster dislocation: a possible mechanism for microbiota homeostasis. PLOS Comput. Biol. 15, e1006986 (2019).
Briliūtė, J. et al. Complex N-glycan breakdown by gut Bacteroides involves an extensive enzymatic apparatus encoded by multiple co-regulated genetic loci. Nat. Microbiol. 4, 1571–1581 (2019).
Orndorff, P. E. et al. Immunoglobulin-mediated agglutination of and biofilm formation by Escherichia coli K-12 require the type 1 pilus fiber. Infect. Immun. 72, 1929–1938 (2004).
Randal Bollinger, R. et al. Human secretory immunoglobulin A may contribute to biofilm formation in the gut. Immunology 109, 580–587 (2003).
Uchimura, Y. et al. Antibodies set boundaries limiting microbial metabolite penetration and the resultant mammalian host response. Immunity 49, 545–559 (2018).
Kawamoto, S. et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152–165 (2014).
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. Immunity 43, 527–540 (2015).
Raskova Kafkova, L. et al. Secretory IgA N-glycans contribute to the protection against E. coli O55 infection of germ-free piglets. Mucosal Immunol. https://doi.org/10.1038/s41385-020-00345-8 (2020).
Forbes, S. J., Eschmann, M. & Mantis, N. J. Inhibition of Salmonella enterica serovar Typhimurium motility and entry into epithelial cells by a protective antilipopolysaccharide monoclonal immunoglobulin a antibody. Infect. Immun. 76, 4137 (2008).
Forbes, S. J. et al. Association of a protective monoclonal IgA with the O antigen of Salmonella enterica serovar Typhimurium impacts type 3 secretion and outer membrane integrity. Infect. Immun. 80, 2454–2463 (2012).
Joglekar, P. et al. Intestinal IgA regulates expression of a fructan polysaccharide utilization locus in colonizing gut commensal Bacteroides thetaiotaomicron. mBio 10, e02321 (2019). This paper shows that intestinal IgA can regulate diet-specific PULs in commensal Bacteroides, supporting the importance of IgA in shaping microbiota metabolism.
Peterson, D. A., McNulty, N. P., Guruge, J. L. & Gordon, J. I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2, 328–339 (2007).
Peterson, D. A. et al. Characterizing the interactions between a naturally primed immunoglobulin A and its conserved Bacteroides thetaiotaomicron species-specific epitope in gnotobiotic mice. J. Biol. Chem. 290, 12630–12649 (2015).
Khan Polymorphic immune mechanisms regulate commensal repertoire. Cell Rep. 29, 541–550 (2019).
Kubinak, J. L. et al. MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat. Commun. 6, 8642 (2015).
Plichta, D. R., Graham, D. B., Subramanian, S. & Xavier, R. J. Therapeutic opportunities in inflammatory bowel disease: mechanistic dissection of host-microbiome relationships. Cell 178, 1041–1056 (2019).
Theodoratou, E. et al. The role of glycosylation in IBD. Nat. Rev. Gastroenterol. Hepatol. 11, 588–600 (2014).
Šimurina, M. et al. Glycosylation of immunoglobulin G associates with clinical features of inflammatory bowel diseases. Gastroenterology 154, 1320–1333.e10 (2018).
Grootjans, J. et al. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response. Science 363, 993–338 (2019).
Huus, K. E. et al. Changes in IgA-targeted microbiota following fecal transplantation for recurrent Clostridioides difficile infection. Gut Microbes 13, 1–12 (2021).
Moon, C. et al. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature 521, 90–93 (2015).
Plaut, A. G., Gilbert, J. V., Artenstein, M. S. & Capra, J. D. Neisseria gonorrhoeae and Neisseria meningitidis: extracellular enzyme cleaves human immunoglobulin A. Science 190, 1103–1105 (1975).
Loomes, L. M., Senior, B. W. & Kerr, M. A. A proteolytic enzyme secreted by Proteus mirabilis degrades immunoglobulins of the immunoglobulin A1 (IgA1), IgA2, and IgG isotypes. Infect. Immun. 58, 1979–1985 (1990).
Yang, C. et al. Fecal IgA levels are determined by strain-level differences in Bacteroides ovatus and are modifiable by gut microbiota manipulation. Cell Host Microbe 27, 467–475 (2020). This paper demonstrates the strain specificity of total IgA induction by human commensal isolates.
Yanagibashi, T. et al. IgA production in the large intestine is modulated by a different mechanism than in the small intestine: Bacteroides acidifaciens promotes IgA production in the large intestine by inducing germinal center formation and increasing the number of IgA+ B cells. Immunobiology 218, 645–651 (2013).
Cerutti, A. Location, location, location: B-cell differentiation in the gut lamina propria. Mucosal Immunol. 1, 8–10 (2008).
Ladinsky, M. S. et al. Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science 363, eaat4042 (2019).
Marcotte, H. & Lavoie, M. C. Oral microbial ecology and the role of salivary immunoglobulin A. Microbiol. Mol. Biol. Rev. 62, 71 (1998).
Simón-Soro, Á. et al. Revealing microbial recognition by specific antibodies. BMC Microbiol. 15, 132 (2015).
Goncalves, P. et al. Antibody-coated microbiota in nasopharynx of healthy individuals and hypogammaglobulinemia patients. J. Allergy Clin. Immunol. 145, 1686–1690 (2020).
Madhwani, T. & McBain, A. J. The application of magnetic bead selection to investigate interactions between the oral microbiota and salivary immunoglobulins. PLoS ONE 11, e0158288 (2016).
Janeway, C. A, Travers, P. Jr, Walport, M., & Shlomchik, M. J. The mucosal immune system. Immunobiology: The Immune System in Health and Disease 5th edn (Garland Science, 2001).
Berbers, R.-M. et al. Low IgA associated with oropharyngeal microbiota changes and lung disease in primary antibody deficiency. Front. Immunol. 11, 1245 (2020).
Armstrong, H. et al. Host immunoglobulin G selectively identifies pathobionts in pediatric inflammatory bowel diseases. Microbiome 7, 1 (2019).
Chen, R. Y. et al. Duodenal microbiota in stunted undernourished children with enteropathy. N. Engl. J. Med. 383, 321–333 (2020).
Costalonga, M. & Herzberg, M. C. The oral microbiome and the immunobiology of periodontal disease and caries. Immunol. Lett. 162, 22 (2014).
Vonaesch, P. et al. Stunted childhood growth is associated with decompartmentalization of the gastrointestinal tract and overgrowth of oropharyngeal taxa. Proc. Natl Acad. Sci. USA 115, E8489–E8498 (2018).
Atarashi, K. et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 358, 359–365 (2017).
Kitamoto, S. et al. The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis. Cell 182, 447–462 (2020).
Shapiro, J. M. et al. Immunoglobulin a targets a unique subset of the microbiota in inflammatory bowel disease. Cell Host Microbe 29, 83–93 (2021).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Sonnenburg, E. D. et al. Diet-induced extinction in the gut microbiota compounds over generations. Nature 529, 212–215 (2016).
Macpherson, A. J., de Agero, M. G. & Ganal-Vonarburg, S. C. How nutrition and the maternal microbiota shape the neonatal immune system. Nat. Rev. Immunol. 17, 508–517 (2017).
Shulzhenko, N. et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med. 17, 1585–1593 (2011).
Goverse, G. et al. Diet-derived short chain fatty acids stimulate intestinal epithelial cells to induce mucosal tolerogenic dendritic cells. J. Immunol. 198, 2172–2181 (2017).
Hosomi, K., Kiyono, H. & Kunisawa, J. Fatty acid metabolism in the host and commensal bacteria for the control of intestinal immune responses and diseases. Gut Microbes 11, 276–284 (2019).
Proietti, M. et al. ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens. Nat. Commun. 10, 250 (2019).
Ren, W. et al. Glutamine-induced secretion of intestinal secretory immunoglobulin A: a mechanistic perspective. Front. Immunol. 7, 503 (2016).
Wu, W. et al. Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol. 10, 946–956 (2017).
Black, R. E. et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 382, 427–451 (2013).
Popkin, B. M., Corvalan, C. & Grummer-Strawn, L. M. Dynamics of the double burden of malnutrition and the changing nutrition reality. Lancet 395, 65–74 (2020).
Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).
Naylor, C. et al. Environmental enteropathy, oral vaccine failure and growth faltering in infants in Bangladesh. EBioMedicine 2, 1759–1766 (2015).
Church, J. A., Parker, E. P., Kirkpatrick, B. D., Grassly, N. C. & Prendergast, A. J. Interventions to improve oral vaccine performance: a systematic review and meta-analysis. Lancet Infect. Dis. 19, 203–214 (2019).
Beatty, D., Napier, B., Sinclair-Smith, C., McCabe, K. & Huges, E. Secretory IgA synthesis in Kwashiorkor. J. Clin. Lab. Immunol. 12, 31–36 (1983).
Bell, R. G., Turner, K. J., Gracey, M. & Others. Serum and small intestinal immunoglobulin levels in undernourished children. Am. J. Clin. Nutr. 29, 392–397 (1976).
Syed, S. et al. Environmental enteropathy in undernourished Pakistani children: clinical and histomorphometric analyses. Am. J. Trop. Med. Hyg. 98, 1577–1584 (2018).
McDonald, C. M. et al. Elevations in serum anti-flagellin and anti-LPS Igs are related to growth faltering in young Tanzanian children. Am. J. Clin. Nutr. 103, 1548–1554 (2016).
Campbell, D. I., Elia, M. & Lunn, P. G. Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation. J. Nutr. 133, 1332–1338 (2003).
Michael, H. et al. Malnutrition decreases antibody secreting cell numbers induced by an oral attenuated human rotavirus vaccine in a human infant fecal microbiota transplanted gnotobiotic pig model. Front. Immunol. 11, 196 (2020).
Rho, S. et al. Protein energy malnutrition alters mucosal IgA responses and reduces mucosal vaccine efficacy in mice. Immunol. Lett. 190, 247–256 (2017).
Goddard, F. G. B. et al. Child salivary SIgA and its relationship to enteric infections and EED biomarkers in maputo, mozambique. Int. J. Env. Res. Public Health 17, 3035 (2020).
Kosek, M. N. et al. Causal pathways from enteropathogens to environmental enteropathy: findings from the MAL-ED birth cohort study. EBioMedicine 18, 109–117 (2017).
Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510, 417–421 (2014).
Syed, S., Ali, A. & Duggan, C. Environmental enteric dysfunction in children. J. Pediatric Gastroenterol. Nutr. 63, 6–14 (2016).
Gilmartin, A. A. & Petri, W. A. Exploring the role of environmental enteropathy in malnutrition, infant development and oral vaccine response. Philos. Trans. R. Soc. B Biol. Sci. 370, 20140143 (2015).
Lagos, R. et al. Effect of small bowel bacterial overgrowth on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR. J. Infect. Dis. 180, 1709–1712 (1999).
Wegorzewska, M. M. et al. Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen. Sci. Immunol. 4, eaau9079 (2019).
Luccia, B. D. et al. Combined prebiotic and microbial intervention improves oral cholera vaccination responses in a mouse model of childhood undernutrition. Cell Host Microbe 27, 899–908.e5 (2020).
Luck, H. et al. Gut-associated IgA+ immune cells regulate obesity-related insulin resistance. Nat. Commun. 10, 3650 (2019). This study shows that high-fat diets lead to reduced SIgA levels in mice and that IgA deficiency reciprocally exacerbates obesity on a high-fat diet.
Muhomah, T. A., Nishino, N., Katsumata, E., Haoming, W. & Tsuruta, T. High-fat diet reduces the level of secretory immunoglobulin A coating of commensal gut microbiota. Biosci. Microbiota Food Health 38, 55–64 (2019).
Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).
Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).
Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Marked alterations in the distal gut microbiome linked to diet-induced obesity. Cell Host Microbe 3, 213–223 (2008).
Ussar, S. et al. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell Metab. 22, 516–530 (2015).
Must, A. et al. The disease burden associated with overweight and obesity. JAMA 282, 1523–1529 (1999).
Pallaro, A. et al. Total salivary IgA, serum C3c and IgA in obese school children. J. Nutr. Biochem. 13, 539–542 (2002).
Tanaka, A. et al. Impaired immunity in obesity: suppressed but reversible lymphocyte responsiveness. Int. J. Obes. Relat. Metab. Disord. 17, 631–636 (1993).
Perruzza, L. et al. Enrichment of intestinal Lactobacillus by enhanced secretory IgA coating alters glucose homeostasis in P2rx7−/− mice. Sci. Rep. 9, 9315 (2019).
Morrison, K. E., Jašarević, E., Howard, C. D. & Bale, T. L. It’s the fiber, not the fat: significant effects of dietary challenge on the gut microbiome. Microbiome 8, 15 (2020).
Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).
Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).
Swidsinski, A. et al. Bacterial overgrowth and inflammation of small intestine after carboxymethylcellulose ingestion in genetically susceptible mice. Inflamm. Bowel Dis. 15, 359–364 (2009).
Gibbons, S. M., Duvallet, C. & Alm, E. J. Correcting for batch effects in case-control microbiome studies. PLoS Comput.Biol. 14, e1006102 (2018).
Kennedy, K., Hall, M. W., Lynch, M. D. J., Moreno-Hagelsieb, G. & Neufeld, J. D. Evaluating bias of illumina-based bacterial 16S rRNA gene profiles. Appl. Environ. Microbiol. 80, 5717–5722 (2014).
Salter, S. J. et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 12, 87 (2014).
Jackson, M. A. et al. Accurate identification and quantification of commensal microbiota bound by host immunoglobulins. Microbiome 9, 33 (2021).
Beller, A. et al. Specific microbiota enhances intestinal IgA levels by inducing TGF-β in T follicular helper cells of Peyer’s patches in mice. Eur. J. Immunol. 50, 783–794 (2020).
Parker, E. P. K., Kampmann, B., Kang, G. & Grassly, N. C. Influence of enteric infections on response to oral poliovirus vaccine: a systematic review and meta-analysis. J. Infect. Dis. 210, 853–864 (2014).
Praharaj, I. et al. Influence of nonpolio enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: a study from South India. J. Infect. Dis. 219, 1178–1186 (2019).
Harris, V. C. et al. Significant correlation between the infant gut microbiome and rotavirus vaccine response in rural Ghana. J. Infect. Dis. 215, 34–41 (2017).
Harris, V. et al. Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan. Gut Microbes 9, 93–101 (2018).
Parker, E. P. K. et al. Influence of the intestinal microbiota on the immunogenicity of oral rotavirus vaccine given to infants in south India. Vaccine 36, 264–272 (2018).
Harris, V. C. et al. Effect of antibiotic-mediated microbiome modulation on rotavirus vaccine immunogenicity: a human, randomized-control proof-of-concept trial. Cell Host Microbe 24, 197–207.e4 (2018).
Oh, J. Z. et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41, 478–492 (2014).
Zhang, B. et al. Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science 346, 861–865 (2014).
Hagan, T. et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell 178, 1313–13283 (2019).
Fix, J. et al. Association between gut microbiome composition and rotavirus vaccine response among Nicaraguan infants. Am. J. Trop. Med. Hyg. 102, 213–219 (2020).
Taniuchi, M. et al. Impact of enterovirus and other enteric pathogens on oral polio and rotavirus vaccine performance in Bangladeshi infants. Vaccine 34, 3068–3075 (2016).
Huda, M. N. et al. Stool microbiota and vaccine responses of infants. Pediatrics 134, e362–e372 (2014).
Shi, Z. et al. Segmented filamentous bacteria prevent and cure rotavirus infection. Cell 179, 644–658.e13 (2019).
Hosomi, K. & Kunisawa, J. Impact of the intestinal environment on the immune responses to vaccination. Vaccine 38, 6959–6965 (2020).
Jong, S. E., de, Olin, A. & Pulendran, B. The impact of the microbiome on immunity to vaccination in humans. Cell Host Microbe 28, 169–179 (2020).
Ca, M. & Mb, T. Composition of gut microbiota and its influence on the immunogenicity of oral rotavirus vaccines. Vaccine 36, 3427–3433 (2018).
The authors are grateful to K. Bauer, to R. Boutin and to our reviewers for their critical reading of this Review. Work in B.B.F.’s lab is supported by a Canadian Institutes for Health Research (CIHR) Foundation Grant. B.B.F. is also a Canadian Institute For Advanced Research (CIFAR) Senior Fellow. K.E.H. was supported by a CIHR Vanier Scholarship and a University of British Columbia Four Year Fellowship. C.P. was supported by a CIHR Postdoctoral Fellowship.
The authors declare no competing interests.
Peer review information
Nature Reviews Immunology thanks G. Nuñez, O. Pabst and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A subclass of IgA in humans, more abundant in the small intestine and in serum, less protease resistant than IgA2.
A subclass of IgA in humans, more abundant in the colon, more protease resistant than IgA1.
Ability of an antibody to bind, nonspecifically, to multiple dissimilar antigenic targets.
- Cross-species reactivity
Ability of an antibody to recognize related antigenic targets on distinct bacterial species or cells.
Bacterial antigens that bind strongly to host immune receptors and induce hyper-proliferation of immune cells.
Antibody-mediated aggregation of target bacteria, due to simultaneous binding of multiple bacterial cells by multivalent antibody. Occurs at high bacterial densities.
- Enchained growth
Antibody-mediated linkage of a bacterium to its own daughter cells during asexual reproduction. Occurs at low bacterial densities.
Microorganisms that are capable of causing adverse host effects in certain contexts.
- Polysaccharide utilization loci
(PULs). Clusters of co-regulated genes in bacteria responsible for the metabolism of polysaccharides.
- Operational taxonomic units
(OTUs). Taxonomic groupings of bacteria based on genetic sequence similarity, often defined as 98% identity of the 16S rRNA gene. Note that modern sequencing pipelines have increasingly replaced OTU with amplicon sequence variant (ASV), which defines every unique genetic sequence as its own taxon (i.e. 100% identity of the 16S rRNA gene).
- Gnotobiotic mice
Germ-free animals colonized with a defined microbiota.
A nutritional supplement that provides a health benefit to the host.
About this article
Cite this article
Huus, K.E., Petersen, C. & Finlay, B.B. Diversity and dynamism of IgA−microbiota interactions. Nat Rev Immunol 21, 514–525 (2021). https://doi.org/10.1038/s41577-021-00506-1
Scientific Reports (2021)
Nature Microbiology (2021)
Spinal fluid IgG antibodies from patients with demyelinating diseases bind multiple sclerosis-associated bacteria
Journal of Molecular Medicine (2021)
Seminars in Immunopathology (2021)
Cellular and Molecular Life Sciences (2021)