Do antibodies select a healthy microbiota?

Abstract

Disruptions to the microbiota can have pathological consequences, which highlights the need to understand the factors that contribute to its stability. Although decades of research have focused on the importance of IgA during pathogenic infection, much of the IgA that is generated in the gut targets the resident commensal microorganisms. Despite this observation, the role of antibodies in regulating microbiota composition remains controversial and poorly understood. Here we propose that antibodies generated in response to microbial colonization of the gut shape the composition of the microbiota to benefit the health of the host through a process that we term antibody-mediated immunoselection (AMIS). Given the exquisite specificity of antibodies and an emerging interest in the use of immunotherapies, we suggest that understanding AMIS of the microbiota will highlight novel uses of antibodies to manipulate microbial communities for therapeutic benefit.

Figure 1 |. Role of immune recognition pathways in antibody-mediated immunoselection of the microbiota.

a | Microbial products can differently influence the development of the antibody repertoire in the gut. This schematic shows how Toll-like receptor (TLR)- and MHC class II-mediated signalling influence T cell-independent and T cell-dependent antibody responses, respectively. T cell-independent antibody responses are promoted by the mitogenic activity of TLR engagement on B cells, and this leads to the generation of relatively low-affinity antibodies with polyreactive specificities. Peptide–MHC class II–T cell receptor (TCR) interactions place more stringent selection on maturing B cells, which reduces the overall diversity of antibody repertoires but results in the generation of high-affinity antibodies with high epitope specificity. b | Two models using species rank abundance curves predict the effect on the microbiota of differential immune signalling in T cell-independent and T cell-dependent antibody responses. The red lines in both panels represent the typical distribution of species in microbiota communities from the gut. A small subset of species numerically dominate the community, but most of the community diversity resides in the long-tailed distribution of rare species. Low-affinity polyreactive antibody repertoires are predicted to bind a wider array of species — that is, have greater antibody coverage of the total microbial community (blue dashed line in left panel) — whereas high-affinity monoreactive antibody repertoires are predicted to bind a more limited array of species — that is, have a narrower range of coverage of the total microbial community (blue dashed line in right panel). By focusing the antibody response against the most abundant species, T cell-dependent antibody responses should favour diversity by constraining the growth of the fastest replicators, which maintains niches for rare and more fastidious microbial species. DC, dendritic cell.

Figure 2 |. Antibody–microorganism interactions that influence antibody-mediated immune-selection of the microbiota.

a | Some microorganisms can secrete enzymes that degrade the secretory component of secretory antibodies, which disrupts the stability of the antibody molecule, rendering it ineffective. b | Some microorganisms may express surface epitopes that bind secretory IgA and facilitate colonization of the mucus lining in the gut. c | Some microorganisms express surface epitopes that are very similar to those on other microorganisms. Antibodies generated against one microorganism can lead to the generation of antibody specificities that cross-react with similar epitopes found on other microorganisms.

Figure 3 |. Potential immunotherapies to modulate antibody-mediated immunoselection in the gut.

Manipulating antibody-mediated immune-selection (AMIS) to establish a healthy gut can be achieved by enhancing or limiting antibody responses to desired antigens. Oral vaccination could be used to specifically limit pathobiont expansion (part a) or to promote biofilm-formation by beneficial species (part b). Exogenous antigens could be delivered into the gut to manage virulence factor expression by pathobionts (part c). Sequestration of antibodies against beneficial microbial products could increase their availability to the host or to other beneficial microorganisms (part d).