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Diversity and dynamism of IgA−microbiota interactions

Abstract

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.

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Fig. 1: Generation of microbiota-reactive IgA through T cell-independent and T cell-dependent pathways.
Fig. 2: Functions of IgA in the gastrointestinal tract.
Fig. 3: Nutrition and IgA–microbiota interactions.

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Acknowledgements

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.

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Correspondence to B. Brett Finlay.

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Glossary

IgA1

A subclass of IgA in humans, more abundant in the small intestine and in serum, less protease resistant than IgA2.

IgA2

A subclass of IgA in humans, more abundant in the colon, more protease resistant than IgA1.

Polyreactivity

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.

Superantigens

Bacterial antigens that bind strongly to host immune receptors and induce hyper-proliferation of immune cells.

Agglutination

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.

Pathobionts

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.

Nutraceutical

A nutritional supplement that provides a health benefit to the host.

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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

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